USOO9023394B2

(12) United States Patent (10) Patent No.: US 9,023,394 B2 Andersen et al. (45) Date of Patent: *May 5, 2015

(54) FORMULATIONS AND METHODS FOR THE 4,330,338 A 5, 1982 Banker CONTROLLED RELEASE OF ACTIVE DRUG 4.389,393 A 6, 1983 Schor et al. 4.404,183 A 9, 1983 Kawata et al. SUBSTANCES 4,449,983 A 5/1984 Cortese et al. 4,503,067 A 3, 1985 Wiedemann et al. (71) Applicant: Egalet Ltd., London (GB) 4,686,212 A 8, 1987 Ducatman et al. 4,824,675 A 4/1989 Wong et al. (72) Inventors: Christine Andersen, Vedbaek (DK); 4,844,984 A 7, 1989 Eckenhoffetal. 4,873,080 A 10, 1989 Bricklet al. Karsten Lindhardt, Haslev (DK); Jan 4,892,742 A 1, 1990 Shah Martin Oevergaard, Frederikssund 4,898,733. A 2f1990 DePrince et al. (DK); Louise Inoka Lyhne-versen, 5,019,396 A 5/1991 Ayer et al. Gentofte (DK); Martin Rex Olsen, 5,068,112 A 11/1991 Samejima et al. Holbaek (DK); Anne-Mette Haahr, 5,082,655 A 1/1992 Snipes et al. 5,102,668 A 4, 1992 Eichel et al. Birkeroed (DK); Pernille Kristine 5,213,808 A 5/1993 Bar Shalom et al. Hoeyrup Hemmingsen, Bagsvaerd 5,266,331 A 11/1993 Oshlack et al. (DK) 5,281,420 A 1/1994 Kelmet al. 5,352.455 A 10, 1994 Robertson (73) Assignee: Egalet Ltd., London (GB) 5,411,745 A 5/1995 Oshlack et al. 5,419,917 A 5/1995 Chen et al. 5,422,123 A 6/1995 Conte et al. (*) Notice: Subject to any disclaimer, the term of this 5,460,826 A 10, 1995 Merrill et al. patent is extended or adjusted under 35 5,478,577 A 12/1995 Sackler et al. U.S.C. 154(b) by 0 days. 5,508,042 A 4/1996 OShlack et al. 5,520,931 A 5/1996 Persson et al. This patent is Subject to a terminal dis 5,529,787 A 6/1996 Merrill et al. claimer. 5,549,912 A 8, 1996 OShlack et al. 5,593,.695 A 1/1997 Merrill et al. (21) Appl. No.: 13/928,135 (Continued) (22) Filed: Jun. 26, 2013 FOREIGN PATENT DOCUMENTS

(65) Prior Publication Data DE 10223844 12/2003 US 2013/02878.49 A1 Oct. 31, 2013 DE 202006O14131 1, 2007 (Continued) Related U.S. Application Data OTHER PUBLICATIONS (63) Continuation of application No. 12/823,067, filed on Jun. 24, 2010, now Pat. No. 8,563,038. Haahr et al. (Poster—Drug abuse resistant, controlled release using Egalet dosage units. Proceedings of the 34th annual Meeting Expo (60) Provisional application No. 61/219,817, filed on Jun. sition of the Controlled Release Society Jul. 7-11 2007).* 24, 2009. Katikaneni et al. (International Journal of Pharmaceutics 123 pp. 119-125 1995).* (30) Foreign Application Priority Data Notification of Transmittal of the International Search Report and the Written Opinion of the International Searching Authority issued Jul. Jun. 24, 2009 (DK) ...... 2009 OO782 8, 2008 in International Application No. PCT/DK2008/000016. International Preliminary Reporton Patentability issued Jul. 16, 2009 (51) Int. Cl. in corresponding International Application No. PCT/DK2008/ A6 IK9/20 (2006.01) 000016, now WO 2008/086804. A6 IK3I/485 (2006.01) (Continued) A6 IK 9/28 (2006.01) (52) U.S. Cl. CPC ...... A61 K9/2086 (2013.01); A61 K3I/485 Primary Examiner — Anoop Singh (2013.01); A61 K9/28 (2013.01); A61 K9/2072 Assistant Examiner — Anna Falkowitz (2013.01) (74) Attorney, Agent, or Firm — Foley & Lardner LLP (58) Field of Classification Search CPC. A61 K31/485; A61 K9/2072: A61 K9/2086; A61 K9/28 (57) ABSTRACT USPC ...... 424/486, 468; 514/282, 411 See application file for complete search history. Controlled release formulations and methods for preparing controlled release formulations for delivery of active drug (56) References Cited substances are described herein. The formulations described herein may be employed to produce pharmaceutical compo U.S. PATENT DOCUMENTS sitions, such as controlled release dosage forms, adjusted to a 2,685,553 A 8, 1954 Carroll et al. specific administration scheme. 3,835,221 A 9, 1974 Fulberth et al. 3,957,523 A 5, 1976 Ohno et al. 4,034,758 A 7, 1977 Theeuwes 38 Claims, 15 Drawing Sheets US 9,023,394 B2 Page 2

(56) References Cited 7,270,831 B2 9, 2007 Oshlack et al. 7,332, 182 B2 2, 2008 Sackler U.S. PATENT DOCUMENTS 7,399,488 B2 T/2008 Hirsh et al. 7,419,686 B2 9, 2008 Kaiko et al. 5,609,885 3, 1997 Rivera et al. 7,476,402 B2 1/2009 Kumar et al. 5,614,218 3, 1997 Olsson et al. 7,510,726 B2 3, 2009 Kumar et al. 5,618,560 4, 1997 Bar-Shalom et al. 7,510,727 B2 3, 2009 Oshlack et al. 5,656,291 8, 1997 Olsson et al. 7,514,100 B2 4/2009 Oshlack et al. 5,656,295 8, 1997 Oshlack et al. 7,666,337 B2 2, 2010 Yang et al. 5,667,805 9, 1997 Merrill et al. 7,749,542 B2 T/2010 Kaiko et al. 5,672,360 9, 1997 Sackler et al. 7,771,707 B2 8, 2010 Hirsh et al. 5,741,524 4, 1998 Staniforth et al. 7,776,314 B2 8, 2010 Bartholomaus et al. 5,866, 161 2, 1999 Childers et al. 7,790,215 B2 9, 2010 Sackler et al. 5,866, 164 2, 1999 Kuczynski et al. 7,842,307 B2 11, 2010 Oshlack et al. 5,869,097 2, 1999 Wong et al. 7,846,476 B2 12/2010 Oshlack et al. 5,879,705 3, 1999 Heafield et al. 7,883,722 B2 2, 2011 Bar-Shalom 5,882,682 3, 1999 Rork et al. 7,883,772 B2 2, 2011 Pourdeyhimi et al. 5,914, 131 6, 1999 Merrill et al. 7,897,080 B2 3, 2011 Yang et al. 5.948,787 9, 1999 Merrill et al. 7,906, 143 B1 3, 2011 Odidi et al. 5,952,005 9, 1999 Olsson et al. 7,943,174 B2 5, 2011 Oshlack et al. 5,958,452 9, 1999 Oshlack et al. 7.972,624 B2 T/2011 Li et al. 5,968,551 10, 1999 Oshlack et al. 7,981,439 B2 T/2011 Kumar et al. 6,046,177 4, 2000 Stella et al. 8,017,148 B2 9, 2011 Sackler 6,066,339 5, 2000 Stark et al. 8,017,150 B2 9, 2011 Yang et al. 6,077,533 6, 2000 Oshlack et al. 8,029,822 B2 10, 2011 Faour et al. 6,077,538 6, 2000 Merrill et al. 8,075,872 B2 12/2011 Arkenau-Maric et al. 6,103.261 8, 2000 Chasin et al. 8, 101,630 B2 1, 2012 Kumar et al. 6,117,453 9, 2000 Seth et al. 8, 105,631 B2 1, 2012 Kaiko et al. 6,143,328 11, 2000 Heafield et al. 8,114,383 B2 2, 2012 BartholomAUs et al. 6,183,778 2, 2001 Conte et al. 8,114,384 B2 2, 2012 Arkenau et al. 6,225,343 5, 2001 Behlet al. 8,133,507 B2 3, 2012 Yum et al. 6,245,351 6, 2001 Nara et al. 8,142,811 B2 3, 2012 Oshlack et al. 6,245,357 6, 2001 Edgren et al. 8, 147,870 B2 4, 2012 Yum et al. 6,267.981 T/2001 Okamoto et al. 8,153,152 B2 4, 2012 Yum et al. 6,267,985 T/2001 Chen et al. 8,168.217 B2 5, 2012 Yum et al. 6,277,384 8, 2001 Kaiko et al. 8,173,152 B2 5, 2012 Crowley et al. 6,284.274 9, 2001 Merrill et al. 8, 182,836 B2 5, 2012 Mehta 6,294,195 9, 2001 Oshlack et al. 8, 192,722 B2 6, 2012 Arkenau-Maric et al. 6,348,216 2, 2002 Kushla et al. 8,231,898 B2 T/2012 Oshlack et al. 6,375,957 4, 2002 Kaiko et al. 8,246,986 B2 8, 2012 Cruz et al. 6,383,471 5, 2002 Chen et al. 8,309,060 B2 11, 2012 Bartholomaus et al. 6,395,299 5, 2002 Babich et al. 8.323,889 B2 12/2012 Arkenau-Maric et al. 6,399,096 6, 2002 Miller et al. 8,329.720 B1 12/2012 King et al. 6,403,579 6, 2002 Heller 8,337,888 B2 12/2012 Wright et al. 6,451,848 9, 2002 Behlet al. 8.338,444 B1 12/2012 King et al. 6.458,772 10, 2002 Zhou et al. 8,354,124 B2 1, 2013 Yum et al. 6,458,824 10, 2002 Iwata et al. 8,361,499 B2 1, 2013 Oshlack et al. 6,475,494 11, 2002 Kaiko et al. 8,367,693 B1 2, 2013 King et al. 6,482.437 11, 2002 Debregeas et al. 8,372.432 B2 2, 2013 Han et al. 6,488,962 12, 2002 Berner et al. 8,377,453 B2 2, 2013 Han et al. 6,488.963 12, 2002 McGinity et al. 8,383,152 B2 2, 2013 Jans et al. 6,491,945 12, 2002 Childers et al. 8,383,154 B2 2, 2013 Bar-Shalom 6,517,866 2, 2003 Am Ende et al. 8,383,155 B2 2, 2013 Bar-Shalom 6,534,085 3, 2003 Zeligs 8,389,007 B2 3, 2013 Wright et al. 6,543,085 4, 2003 Holsten et al. 8,389,008 B2 3, 2013 Baichwal et al. 6,562.375 5/2003 Sako et al. 8,394.407 B2 3, 2013 Vergnault et al. 6,572.885 6, 2003 Oshlack et al. 8,394.408 B2 3, 2013 Han et al. 6,599,531 T/2003 Kushla et al. 8,409,616 B2 4, 2013 Kumar et al. 6,607,751 8, 2003 Odidi et al. 8,415,401 B2 4, 2013 Yum et al. 6,632,832 10, 2003 Burman et al. 8.420,056 B2 4, 2013 Arkenau-Maric et al. 6,673,816 1, 2004 Esswein et al. 8.420,120 B2 4, 2013 Yum et al. 6,685,964 2, 2004 Bartholomaeus et al. 8.425,933 B2 4, 2013 Mehta 6,696,066 2, 2004 Kaiko et al. 8.445,018 B2 5, 2013 Habib et al. 6,709,678 3, 2004 Gruber 8.449,909 B2 5, 2013 Hirsh et al. 6,730,326 5, 2004 Beyer et al. 8.449,914 B2 5, 2013 Fischer et al. 6,733,783 5, 2004 Oshlack et al. 8,460,640 B2 6, 2013 Vinson et al. 6,757,558 6, 2004 Lange et al. 8.465,776 B2 6, 2013 Hoarau 6,787,156 9, 2004 Bar-Shalom 8,470.361 B2 6, 2013 Pettersson 6,800,668 10, 2004 Odidi et al. 8,476,291 B1 T/2013 King et al. 6,837,696 1/2005 Sowden et al. 8,486,423 B2 T/2013 Brough et al. 6,852,337 2, 2005 Gabel et al. 8,486,448 B2 T/2013 Rahmouni et al. 6,960,357 11/2005 Chopra 8,486,449 B2 T/2013 Rahmouni et al. 7,060,293 6, 2006 Oshlack et al. 8.491,935 B2 T/2013 Mehta et al. 7,063,864 6, 2006 Marechal et al. 8,501,160 B2 8, 2013 Cailly-Dufestel et al. 7,090,867 8, 2006 Odidi et al. 8,506,998 B2 8, 2013 Miller et al. 7,144,587 12, 2006 Oshlack et al. 8,524,275 B2 9, 2013 Oshlack et al. 7,172,767 2, 2007 Kaiko et al. 8,524.277 B2 9, 2013 Edgren et al. 7,201.920 4, 2007 Kumar et al. 8,529,848 B2 9, 2013 Danehy et al. 7,214,315 5/2007 Shumway 8,529,948 B1 9, 2013 Wright et al. US 9,023,394 B2 Page 3

(56) References Cited 2007/0048228 A1 3/2007 Arkenau-Maric et al. 2007/0065.364 A1 3/2007 OShlack et al. U.S. PATENT DOCUMENTS 2007/006551.0 A1 3/2007 Odidi et al. 2007/O1224.55 A1 5/2007 Myers et al. 8,541,026 B2 9/2013 Qiu et al. 2007, 0183980 A1 8/2007 Arkenau-Maric et al. 8,551,520 B2 10/2013 Oshlack et al. 2007. O190142 A1 8, 2007 Breitenbach et al. 8,563.038 B2 10, 2013 Andersen et al. 2007/0224129 A1 9, 2007 Guimberteau et al. 8.603526 B2 13/2013 Tygeseneral 2007/0231268 A1 10/2007 Emigh et al. 8.609. 143 B2 12/2013 Fischer et al. 2007,0259033 A1 11/2007 Cruz et al. 8,609.683 B2 12/2013 Wright et al. 2007/0259045 A1 11/2007 Mannion et al. 8,617.605 B2 12/2013 Fischer et al. 2007/0264326 A1 11/2007 Guimberteau et al. 8,637,540 B2 1/2014 Kumar et al. 2007/0264346 A1 11/2007 Guimberteau et al. 8.647,667 B3 2.2014 Oshiacket al. 2007/0275,062 A1 11/2007 OShlack et al. 8,685447 B2 4/2014 Rahmouni et al. 2007/0281 003 A1 12/2007 Fuisz et al. 8,703.189 B2 4/2014 Tomohira 2007/028.1007 A1 12/2007 Jacob et al. 8,715,721 B2 5 2014 Oshiacket al. 2008/0026052 A1 1/2008 Schoenhard 8.765.178 B2 7/2014 Parikhet al. 2008/0152595 A1 1/2008 Emigh et al. 8,808,745 B2 8/2014 Fischer et al. 2008/0031901 A1 2/2008 Qiu et al. 8,821,928 B2 9/2014 Hemmingsen et al. 2008/0044454 A1 2/2008 Yang et al. 8,877.241 B2 11/2014 Fischer et al. 2008, OO63725 A1 3/2008 Guimberteau et al. 2001/003.6959 A1 11, 2001 Gabel et al. 2008, OO69891 A1 3, 2008 Habib et al. 2001/003.6960 A1 11/2001 Decker et al. 2008/0075771 A1 3/2008 Vaughn et al. 2001/0053791 A1 12/2001 Babcock et al. 2008.0102121 A1 5/2008 Devane et al. 2002fOO54911 A1 5, 2002 Oh 2008.0113025 A1 5/2008 Devane et al. 2002/01 19197 A1 8/2002 Dyar et al. 2008. O166405 A1 7, 2008 Mehta 2003.0035836 A1 2/2003 Shanghviet al. 2008. O166407 A1 7/2008 Shalaby et al. 2003.0068375 A1 4/2003 Wright et al. 2008.0193540 A1 8, 2008 Soula et al. 2003/0077320 A1 4, 2003 Childers et al. 2008/0200493 Al 8, 2008 Drewes et al. 2003/009 1635 A1 5/2003 Baichwal et al. 2008/023.4352 A1 9, 2008 Fischer et al. 2003.01.18641 A1 6/2003 Maloney et al. 2008/0247959 A1 10, 2008 Bartholomaus et al. 2003/0129231 A1 7/2003 Oshlack et al. 2008/024811.0 A1 10, 2008 Pettersson et al. 2003/O133976 A1 7/2003 Pather et al. 2008/0248113 A1 10, 2008 Bartholomaus et al. 2003/02O3055 A1 10, 2003 Rao et al. 2008/0254.122 A1 10, 2008 Fischer et al. 2003,0224051 A1 12, 2003 Fink et al. 2008/0254123 A1 10, 2008 Fischer et al. 2004/0010000 A1 1/2004 Ayer et al. 2008/0254124 A1 10, 2008 Bar-Shalom 2004/0028733 A1 2/2004 Tracy et al. 2008/0268.057 A1 10, 2008 Andersen et al. 2004.0089605 A1 5/2004 Brandt et al. 2008/0299.199 A1 12/2008 Bar Shalom et al. 2004/009 1529 A1 5/2004 Edgren et al. 2008/0311187 A1 12/2008 Ashworth et al. 2004.0102476 A1 5, 2004 Chan et al. 2008/0311197 A1 12/2008 Arkenau-Maric et al. 2004/O115262 A1 6, 2004 Jao et al. 2008/0311205 A1 12/2008 Habib et al. 2004/O151772 A1 8/2004 Andersen et al. 2008/0317854 A1 12/2008 Arkenau et al. 2004/0202717 A1 10, 2004 Mehta 2009,0004267 A1 1/2009 Arkenau-Maric et al. 2004/0204474 A1 10, 2004 Decker et al. 2009,0005408 A1 1/2009 Arkenau-Maric et al. 2004/0213849 A1 10, 2004 Sowden et al. 2009.001101.6 A1 1/2009 Cailly-Dufestel et al. 2004/022O250 A1 11, 2004 Oh et al. 2009/0022790 A1 1/2009 Flath et al. 2004/0224020 A1 11/2004 Schoenhard 2009/0022798 A1 1/2009 Rosenberg et al. 2004/0234.602 A1 11/2004 Fischer et al. 2009/0041838 A1 2/2009 Guimberteau et al. 2004/0253310 A1 12/2004 Fischer et al. 2009,0081290 A1 3/2009 McKenna et al. 2005, OO19399 A1 1/2005 Fischer et al. 2009.0099151 A1 4, 2009 Jain et al. 2005, OO19405 A1 1/2005 Bar-Shalom 2009/0123.386 Al 5/2009 Young, 2005/0020613 A1 1/2005 Boehmet al. 2009, O155357 A1 6, 2009 Muhuri 2005, 0037068 A1 2/2005 Massironi 2009, O169631 A1 7/2009 Zamloot et al. 2005.0053655 A1 3/2005 Yang et al. 2009/0202634 A1 8, 2009 Janset al. 2005/OO74493 A1 4/2005 Mehta et al. 2009, O232887 A1 9, 2009 Odidi et al. 2005.0089569 A1 4/2005 Bar-Shalom 2009,0274759 A1 11/2009 Bar-Shalom et al. 2005.0089570 A1 4/2005 Cruz et al. 2009,0298862 A1 12/2009 Yum et al. 2005/OO95295 A1 5/2005 Maggiet al. 20090317355 A1 12/2009 Roth et al. 2005/0106249 A1 5/2005 Hwang et al. 2010.0099696 A1 4/2010 Soscia et al. 2005/0152843 A1 7/2005 Bartholomaus et al. 2010/0151028 A1 6.2010 Ashworth et al. 2005. O158382 A1 7/2005 Cruz et al. 2010, 0168148 A1 7/2010 Wright et al. 2005, 0163837 A1 7, 2005 Boehmet al. 2010/0172989 A1 7, 2010 Roth et al. 2005, 0169992 A1 8, 2005 Jao et al. 2010/0203129 A1 8/2010 Andersen et al. 2005/0236741 A1 10, 2005 Arkenau et al. 2010/0203130 A1 8/2010 Tygesen et al. 2006/0002860 A1 1/2006 Bartholomaus et al. 2010/0204259 A1 8/2010 Tygesen et al. 2006/00398.64 A1 2/2006 Bartholomaus et al. 2010/0239667 Al 9, 2010 Hemmingsen et al. 2006, O110327 A1 5/2006 Emigh et al. 2010/0266701 A1 10, 2010 Guimberteau et al. 2006/O165790 A1 7/2006 Walden et al. 2010/0291205 A1 11/2010 Downie et al. 2006/0177380 A1 8/2006 Emigh et al. 2011/0008424 A1 1/2011 Chang et al. 2006/0177507 A1 8, 2006 Faour et al. 2011/0020451 A1 1/2011 Bartholomäus et al. 2006/0188447 A1 8/2006 Arkenau-Maric et al. 2011/003893.0 A1 2/2011 Barnscheid et al. 2006/0193782 A1 8/2006 Bartholomaus et al. 2011/0077238 A1 3/2011 Leech et al. 2006, O1939 12 A1 8, 2006 KetSela et al. 2011 0104214 A1 5, 2011 Oshlack et al. 2006, O193914 A1 8, 2006 Ashworth et al. 2011/O136847 A1 6, 2011 Chan et al. 2007, OOO36.16 A1 1/2007 Arkenau-Maric et al. 2011/O142905 A1 6/2011 Bar-Shalom et al. 2007/OOO3617 A1 1/2007 Fischer et al...... 424/468 2011 O159100 A1 6/2011 Andersen et al. 2007, OOO3620 A1 1/2007 Marechal et al. 2011/O165248 A1 7/2011 Machonis 2007/OOO4797 A1 1/2007 Weyers et al. 2011/O195989 A1 8/2011 Rudnic et al. 2007/0020331 A1 1/2007 Gold et al. 2011/0200681 A1 8, 2011 Habib et al. 2007/0042044 A1 2/2007 Fischer et al. 2011/02007 15 A1 8, 2011 FuisZ. et al. US 9,023,394 B2 Page 4

(56) References Cited 2014/0050787 A1 2, 2014 Tygesen et al. 2014/O120164 A1 5, 2014 Fischer et al. U.S. PATENT DOCUMENTS 2014/O155388 A1 6, 2014 Brzeczko et al. 2014,0193490 A1 T/2014 Schoenhard 2011/022.9526 A1 9, 2011 Rosenberg et al. 2014/0221416 A1 8, 2014 Guido et al. 2011/0229533 A1 9, 2011 Edgren et al. 2014/0271848 A1 9, 2014 Guido et al. 2011/0287O93 A1 11, 2011 Schoenhard 2014/0271849 A1 9, 2014 Raman 2012,0009129 A1 1, 2012 Brzeczko 2014/0271896 A1 9, 2014 Abu Shmeis 2012, OO15007 A1 1, 2012 Bredenberg et al. 2014/0275143 A1 9, 2014 Devarakonda et al. 2012,0059065 A1 3/2012 Barnscheid et al. 2014/0294947 A1 10, 2014 Reilly et al. 2012,0065220 A1 3/2012 Barnscheid et al. 2012/0135075 A1 5, 2012 Mohammad FOREIGN PATENT DOCUMENTS 2012/0136021 A1 5, 2012 Barnscheid et al. 2012fO164220 A1 6, 2012 Huang DE 10200605,7364 6, 2008 2012fO2O1761 A1 8, 2012 Sackler EP O 068838 B1 9, 1986 2012/0202838 A1 8, 2012 Ghosh et al. EP O435,726 8, 1991 2012/0202839 A1 8, 2012 Emigh et al. EP O493513 7, 1992 2012/O214777 A1 8, 2012 Crowley et al. EP O406315 11, 1992 2012fO225122 A1 9, 2012 Hamed et al. EP O 908181 4f1999 2012fO251637 A1 10, 2012 Bartholomäus et al. EP 1 O27 888 8, 2000 2012,0321674 A1 12, 2012 Vachon et al. EP O 335560 1, 2002 2012,0321713 A1 12, 2012 Han et al. EP 1213 014 A2 6, 2002 2012,0321716 A1 12, 2012 Vachon et al. EP 1371 360 5, 2005 2013, OOO5823 A1 1, 2013 Emigh et al. EP 154767O 6, 2005 2013, OO11479 A1 1, 2013 Angeli et al. GB 1430684 3, 1976 2013, OO12533 A1 1, 2013 Oshlack et al. GB 2170 104 T 1986 2013/0022646 A1 1, 2013 Rudnic et al. GB 2182559 5, 1987 2013,0028.177 A1 1, 2013 Koskela et al. JP 6O255719 12/1985 2013,002897O A1 1, 2013 Schwier et al. JP 07/100.191 4f1995 2013,0028972 A1 1, 2013 Schwier et al. WO WO 86.04817 8, 1986 2013, OO30561 A1 1, 2013 Imanari et al. WO WO 89,09066 10, 1989 2013,0084.333 A1 4, 2013 Dicket al. WO WO90,08536 8, 1990 2013/0090349 A1 4, 2013 Gei?ler et al. WO WO91,040 15 4f1991 2013/O122087 A1 5, 2013 Habib et al. WO WO92,09270 6, 1992 2013/O122101 A1 5, 2013 Habib et al. WO WO93/10765 6, 1993 2013/0129825 A1 5, 2013 Billoet et al. WO WO95/22962 8, 1995 2013/0129826 A1 5, 2013 Gei?ler et al. WO 96.OOO66 A1 1, 1996 2013/0171075 A1 T/2013 Arkenau-Maric et al. WO 96,08253 A1 3, 1996 2013/0171257 A1 T/2013 Kumar et al. WO 97.33566 A2 9, 1997 2013,0195981 A1 8, 2013 Pettersson WO WO99,05105 2, 1999 2013,0195982 A1 8, 2013 Pettersson WO 99.44591 A1 9, 1999 2013/0209557 A1 8, 2013 Barnscheid WO WO99,51208 10, 1999 2013/0209560 A1 8, 2013 Hamed et al. WO WOOOf 41704 T 2000 2013/0217716 A1 8, 2013 Wright et al. WO WOO1/35958 5, 2001 2013/0225697 A1 8, 2013 Barnscheid et al. WO WOO1/51035 T 2001 2013/0230596 A1 9, 2013 Mehta WO WOO1/51036 T 2001 2013,0245055 A1 9, 2013 Wright et al. WO WOO 1/74357 10, 2001 2013,025 1759 A1 9, 2013 Jans et al. WO 02/056861 A2 T 2002 2013,025 1796 A1 9, 2013 McKenna et al. WO WO O2/O65834 8, 2002 2013/025 1797 A1 9, 2013 McKenna et al. WO O2/O87512 A2 11, 2002 2013,025 1798 A1 9, 2013 McKenna et al. WO WO O2/O92078 11, 2002 2013,025 1799 A1 9, 2013 McKenna et al. WO WO 03/024426 3, 2003 2013,025 1800 A1 9, 2013 McKenna et al. WO WOO3,O24429 3, 2003 ...... A61K9/22 2013,025 1801 A1 9, 2013 McKenna et al. WO WOO3,O24430 3, 2003 2013,025 1802 A1 9, 2013 McKenna etal WO WOO3,O26613 4/2003 2013,025 1806 A1 9, 2013 Andrade de Freitas et al. WO WOO3,O75897 9, 2003 2013/0259938 A1 10, 2013 McKenna et al. WO WOO3,082204 10, 2003 2013/0259939 A1 10, 2013 McKenna et al. WO 03/092648 A1 11, 2003 2013/0259940 A1 10, 2013 McKenna et al. WO 03.10.1384 A2 12/2003 2013,026.0015 A1 10, 2013 McKenna et al. WO 2004/OO2447 A2 1, 2004 2013,0261143 A1 10, 2013 Wright et al. WO WO 2004/041252 5, 2004 2013/0273.162 A1 10, 2013 Li et al. WO 2004/047839 A1 6, 2004 2013/028O176 A1 10, 2013 Diezi et al. WO 2004/054542 A2 T 2004 2013,0280338 A1 10, 2013 Wening et al. WO 2004/056337 A2 T 2004 2013,0281480 A1 10, 2013 Yum et al. WO 2004/09 1512 A2 10, 2004 2013/0287845 A1 10, 2013 Yum et al. WO WO 2004/084868 10, 2004 2013/02878.50 A1 10, 2013 Andersen et al. WO WO 2004/084869 10, 2004 2013,0295168 A1 11, 2013 Yum et al. WO WO 2004/093819 11, 2004 2013/0303494 A1 11, 2013 Wright et al. WO WO 2004/093843 11, 2004 2013/0303623 A1 11, 2013 Barnscheid et al. WO 2005.000310 A1 1, 2005 2013/0317049 A1 11, 2013 Yum et al. WO WO 2005/007074 1, 2005 2013/0317051 A1 11, 2013 Oshlack et al. WO 2005/O16314 A1 2, 2005 2013,0320592 A1 12, 2013 Arkenau-Maric et al. WO WO 2005/O16313 2, 2005 2013/0337059 A1 12, 2013 Yum et al. WO 2005/034859 A2 4/2005 2013/0337O60 A1 12, 2013 Yum et al. WO 2005/053587 A1 6, 2005 2013,0344142 A1 12, 2013 Rahmouni et al. WO 2005/063206 A1 7/2005 2013,0344143 A1 12, 2013 Rosenberg et al. WO 2005/063214 A1 7/2005 2014/0010873 A1 1, 2014 Tygesen et al. WO 2005,102286 A1 11, 2005 2014/OO3O327 A1 1, 2014 McKenna et al. WO 2006/0O2883 A1 1, 2006 US 9,023,394 B2 Page 5

(56) References Cited WO 2013/038268 A1 3f2013 WO WO 2013/030.177 3, 2013 FOREIGN PATENT DOCUMENTS WO 2013/050539 A2 4/2013 WO 2013,057570 A2 4/2013 WO 2006/0O2884 A1 1/2006 WO 2013,072395 A1 5, 2013 WO 2006/0O2886 A1 1, 2006 WO 2013,077851 A1 5, 2013 WO WO 2006/O15682 2, 2006 WO 2013,084059 A1 6, 2013 WO 2006/030402 A2 3, 2006 WO WO 2013/128276 9, 2013 WO 2006/031209 A1 3, 2006 WO WO 2013, 171146 11, 2013 WO WO 2006/026504 3, 2006 WO WO 2014/091437 6, 2014 WO WO 2006/058249 6, 2006 WO 2006/088305 A1 8/2006 M OTHER PUBLICATIONS WO 2006/089843 A2 8, 2006 Notification of Transmittal of the International Search Report and the WO 2006,103418 A1 10, 2006 Written Opinion of the International Searching Authority issued Apr. WO WO 2006,103551 10, 2006 21, 2010 in International Application No. PCT/EP2010/000728. WO WO 2006/106344 10, 2006 International Preliminary Reporton Patentability issued Aug. 6, 2011 WO WO 2005,107713 11, 2006 in corresponding International Application No. PCT/EP2010/ WO WO 2006/128471 12/2006 000728, now WO 2010/089132. WO 2007/O14061 A2 2, 2007 Notification of Transmittal of the International Search Report and the W. 38783 s A: 339, Written Opinion of the International Searching Authority issued May WO 2007/106550 A2 9, 2007 28, 2010 in International Application No. PCT/DK2010/000019. WO 2007 112285 A2 10/2007 International Preliminary Reporton Patentability issued Aug. 6, 2011 WO 2007 112286 A2 10/2007 in corresponding International Application No. PCT/DK2010/ WO 2007/133583 A2 11/2007 000019, now WO 2010/088911. WO 2007 1351.93 A2 11/2007 Notification of Transmittal of the International Search Report and the WO WO 2007 131357 11, 2007 Written Opinion of the International Searching Authority issued Jan. WO 2007 150074 A2 12/2007 28, 2009 in International Application No. PCT/US2008/056910. WO 2007 150075 A2 12/2007 Notification of Transmittal of the International Search Report and the WO WO 2008/O23261 2, 2008 Written Opinion of the International Searching Authority issued Feb. WO 2008/027442 A2 3, 2008 6, 2010 in International Application No. PCT/DK2010/050016. W 398, A. 33. International Type Search Report issued Jun. 17, 2009 in Interna WO 2008/0684.71 A1 6, 2008 tional Application No. DK 200900 1925. WO WO 2008/086804 T 2008 Office Action issued Dec. 17, 2012 in co-pending U.S. Appl. No. WO 2008/10O375 A2 8, 2008 12/701,429, now US 2010/0203130. WO 2008.107149 A2 9, 2008 Response to First Office Action filed Mar. 13, 2013 in in co-pending WO WO 2008. 148798 12/2008 U.S. Appl. No. 12/701,429, now US 2010/0203130. WO 2009/035474 A1 3, 2009 First Office Action issued Feb. 24, 2012 in co-pending U.S. Appl. No. WO 2009,075782 A1 6, 2009 12/701,248. WO 2009,076236 A2 6/2009 Response to first Office Action filed Jun. 21, 2012 in co-pending U.S. WO 2009,076764 A1 6, 2009 Appl. No. 12/701.248. W. 299; A. 23: Second Office Action issued Jul. 20, 2012 in co-pending U.S. Appl. WO 2009/104838 A1 8, 2009 No. 12/701.248. WO 2009, 114648 A1 9, 2009 Response to Jul. 20, 2012 Office Action filed Oct. 22, 2012 in co WO 2010/017821 A1 2/2010 pending U.S. Appl. No. 12/701.248. WO WO 2010/022726 3, 2010 Interview Summary issued Dec. 12, 2012 in co-pending U.S. Appl. WO WO 2010/032128 3, 2010 No. 12/701.248. WO WO 2010/032128 A1 3, 2010 Preliminary Amendment filed Jul. 13, 2009 unco-pending U.S. Appl. WO 2010/066034 A1 6, 2010 No. 12/523,045. WO 2010/069050 A1 6, 2010 Office Action issued Oct. 26, 2011 in U.S. Appl. No. 12/523,045, now WO 2010/083894 A1 T 2010 US 2010/0291205. WO WO 2010.083843 T 2010 Response to Oct. 26, 2011 Office Action filed Feb. 21, 2012 in WO WO 2010/088911 8, 2010 co-pending U.S. Appl. No. 12/523,045, now US 2010/0291205. W WO 38885 A2 S388 Office Action issued May 24, 2012 in U.S. Appl. No. 12/523,045. WO 2010, 151741 A1 12/2010 now 2010/0291205. WO 2011 0096O2 A1 1, 2011 Response to May 24, 2012 Office Action filed Aug. 7, 2012 in U.S. WO 2011 009603 A1 1, 2011 Appl. No. 12/523,045, now US 2010/0291205. WO 2011 0096.04 A1 1, 2011 Interview Summary issued Dec. 14, 2012 in U.S. Appl. No. WO 2011/041414 A1 4/2011 12/523,045, now US 2010/0291205. WO 2011/068723 A1 6, 2011 First Office Action issued Mar. 7, 2013 in co-pending U.S. Appl. No. WO 2011/079248 A1 6, 2011 12/602,953, now US 2010/0239667. WO 2011 106416 A2 9, 2011 First Office Action issued Apr. 11, 2012 in co-pending U.S. Appl. No. WO 2012/028317 A1 3f2012 12,694,197, now US 2010/0203129. WO 2012/028318 A1 3, 2012 Response to First Office Action filed Jul. 11, 2012 in co-pending U.S. W. 58-38. A. 33: Appl. No. 12694,197, now US 2010/0203129. WO 2012/061779 A1 5, 2012 Final Office Action issued Sep. 14, 2012 in co-pending U.S. Appl. WO 2012/076907 A2 6, 2012 No. 12/694,197, now US 2010/0203129. WO 2012/080833 A2 6, 2012 Response to Final Office Action filed Mar. 13, 2013 in co-pending WO 2012,085656 A2 6, 2012 U.S. Appl. No. 12/694,197, now US 2010/0203129. WO 2012,085657 A2 6, 2012 First Office Action issued Nov. 14, 2011 in U.S. Appl. No. WO 2012/112952 A1 8, 2012 12/823,067, now US 2011/0159100. WO 2012/131463 A2 10/2012 Response to Nov. 14, 2011 Office Action filed May 14, 2012 in WO 2013/017234 A1 2, 2013 co-pending U.S. Appl. No. 12/823,067, now US 2011/0159 100. WO 2013/017242 A1 2, 2013 Final Office Action issued Sep. 10, 2012 in U.S. Appl. No. WO 2013/038267 A1 3, 2013 12/823,067, now US 2011/0159100. US 9,023,394 B2 Page 6

(56) References Cited Response to Sep. 9, 2013 Office Action filed Dec. 9, 2013 in U.S. Appl. No. 12/523,045. OTHER PUBLICATIONS Preliminary Amendment filed Dec. 3, 2009 in U.S. Appl. No. 12/602,953. Interview Summary issued Dec. 20, 2012 in U.S. Appl. No. Response to Non Final Office Action filed Sep. 6, 2013 in U.S. Appl. 12/823,067, now US 2011/0159100. No. 12/602,953. Response to Sep. 10, 2012 Final Office Action filed Jan. 10, 2013 in Final Office Action issued Dec. 19, 2013 in U.S. Appl. No. U.S. Appl. No. 12/823,067, now US 2011/0159100. 12/602,953. Brannan, et al. (Geometry 2nd Edition. Cambridge University Press: NY; 2012 p. 78). Amendment After Allowance filed Jul. 29, 2013 in U.S. Appl. No. Camu & Vanlersberghe, “Pharmacology of Systemic Analgesics.” 12/823,067. Best Practice and Research Clinical Anesthesiology, 2002; 16(4): Notice of Allowance issued Sep. 9, 2013 in U.S. Appl. No. 475-88. 12/823,067. Dahlstrom, et al., “Patient-Controlled Analgesic Therapy, Part IV: Preliminary Amendment filed Jun. 26, 2013 in U.S. Appl. No. Pharmacokinetics and Analgesic Plasma Concentrations of Mor 13/928, 190. phine.” Clinical Pharmacokinetics, 1982; 7:266-79. Preliminary Amendment filed Jul. 29, 2013 in U.S. Appl. No. Fischer, et al., “Nonmedical Use of Prescription Opioids: Furthering 13/933,053. a Meaningful Research Agenda.” J. Pain. 9:6, 2008 490-493. Supplemental Amendment filed Jul. 11, 2013, in U.S. Appl. No. Graves et al., “Relationship Between Plasma Morphine Concentra 12/523,045. tions and pharmacologic Effects in Postoperative Patients. Using Notice of Allowance issued Jun. 11, 2013, in U.S. Appl. No. Patient-Controlled Analgesia.” Clinical Pharmacology, 1985; 4:41-7. 12/823,067. Haahr, et al. (Poster—Drug Abuse Resistant, Controlled Release Notice of Allowance issued Jul. 24, 2013, in U.S. Appl. No. using Egalet Dosage Units. Proceedings of the 34th Annual Meeting 12/701,429. Exposition of the Controlled Release Society Jul. 7-11 2007). Amendment after Notice of Allowance filed Aug. 26, 2013, in U.S. Hemmingsen, et al., “Drug Abuse Resistant, Controlled Release, Appl. No. 12/701,429. Using Egalet Dosage Units' poster. Published Jun. 28, 2007. Bravo et al., “In-vitro studies of diclofenac sodium controlled-release Katikaneni, et al. Ethylcellulose Matrix controlled Release Tablets of from biopolymeric hydrophilic matrices.” J. Pharmaceutical Sci a Water-Soluable Drug. International Journal of Pharmaceutics 123 ence, vol. 5, No. 3, pp. 213-219 (2002). pp. 119-125 1995. L. Qui, et al., “Design Core-Shelled Polymer Cylinder for Potential The Condensed Chemical Dictionary, “mixture.” 9th edition, p. 584 Programmable Drug Delivery.” Int. J. Pharm., 2001; 2 19:151-160. (1977). Meyer, et al., “Awareness Topic: Mitigating the Risks of Ethanol Giunchedi et al., “Hydrophilic matrices for the extended release of a Induced Dose Dumping from Oral Sustained/Controlled Release model drug exhibiting pH-dependent solubility.” International Jour Dosage Forms.” FDA's ACPS Meeting, Oct. 2005. nal of Pharmaceutics, vol. 85, pp. 141-147 (1992). National Institute on Drug Abuse, Monitoring the Future, “National Hoshi et al., Cellulose and its Derivatives, pp. 24-25 (1992). Results on Adolescent Drug Use Overview of Key Findings 2009.” Miyazaki et al., “In situ-gelling gellan formulations as vehicles for http://www.monitoringthefuture.org/ (Originally Published in May oral drug delivery.” J. Control Release, vol. 60, pp. 287-295 (1999). 2010). Rowe et al., “Glycerin.” Handbook of Pharmaceutical Excipients, National Institute on Drug Abuse, Monitoring the Future, “National Pharmaceutical Presse, 4' edition, pp. 257-258 (2003). Results on Adolescent Drug Use Overview of Key Findings 2008.” Yamakita et al., “In Vitrofin Vivo Evaluation of Two Series of http://www.samhsa.gov/ (Originally Published in May 2009). TA5707F Controlled Release Matrix Tablets Prepared with National Institute on Drug Abuse, 2008 http://www.nida.nih.gov/ Hydroxypropyl Methyl Cellulose Derivatives with Entero-Soluble or dmgpages/prescription.html (Last Accessed on Jul. 15, 2008). Gel-Formation Properties.” Biol. Pharm. Bull, vol. 18, No. 10, pp. Raehhal & Bohn, "Mu Opioid Receptor Regulation and Opiate 1409-1416 (1995). Responsiveness.” The AAPS Journal 2005; 7(3): Article 60. Wikipedia, “Phosphoric Acid.” http://en.wikipedia.org/wiki/Phos (www.rxlist.com/miralax-drug.htm) as referenced Oct. 19, 2011. phoric acid downloaded May 10, 2012. Roberts, et al. “Enterohepatic Circulation: Physiological, Hoffman et al., “Phase Diagrams and Aggregation Behavior of Poly Pharmacokinetic and Clinical Implications.” Clin. Pharmacokinet. (oxyethylene)-Poly(oxyethelene) Tribolock Copolymers in Aqueous 41(10), 751-790 (2002). Andersen et al., “Formulations and Methods for the Controlled Solutions.” Macromolecules, vol. 27, pp. 4145-4159, 1994. Release of Active Drug Substances.” Office Action dated Feb. 6. Packer et al., “Molecular Aspects of a-Tocotrienol Antioxidant 2014. Action and Cell Signaling.” Journal of Nutrition, vol. 131, No. 2, pp. Tygesen et al., “Abuse-Deterrent Pharmaceutical Compositions For 369S-373S, 2001. Controlled Release.” U.S. Appl. No. 14/249,965, filed Apr. 10, 2014, Marvola et al., “Enteric polymers as binders and coating materials in 91 pages. multiple-unit site-specific drug delivery systems.” European Journal Hemmingsen et al., “Development of a New Type of Prolonged of Pharmaceutical Sciences, vol. 7, pp. 259-267, 1999. release Hydrocodone Formulation Based on Egalet(R) ADPREM Dubbs et al., “Solubility of Vitamin E(O-Tocopherol) and Vitamin K Technology Using In vivo-In Vitro Correlation.” Pharmaceutics, (Menadione) in Ethanol-Water Mixture.” J. Chem. Eng. Data, vol. 3:73-87, 2011. 43, pp. 590-591, 1998. Roberts et al., “Enterohepatic circulation: physiological, Merck Index (9' ed.) Entry No. 9681 for Vitamin E. p. 1290, 1976. pharmacokinetic and clinical implications.” Clin Pharmacokinet Varshosaz et al., “Use of enteric polymers for production of 4 I (10):751-90, 2002. (Abstract). microspheres by extrusion-spheronization.” Pharmaceutica Acta International Preliminary Report on Patentability issued Sep. 30. Helvetiae, vol. 72, pp. 145-152. 1997. 2009 in International Application No. PCT/EP2008/056910. International Search Report issued on Jul. 8, 2008 in application No. International Preliminary Report on Patentability issued Apr. 12, PCT/DK2008/000016 (corresponding to US 8,603,526). 2011 in International Application No. PCT/DK2010/050016. International Search Report issued on Oct. 20, 2009 in application International Search Report issued Oct. 20, 2009 in International No. PCT, DK2009/000192. Application No. PCT/DK2009/000192. International Search Report issued on Apr. 21, 2010 in application International Preliminary Reporton Patentability issuedMar. 1, 2011 No. PCT/EP2010/00728 (corresponding to US 2010/0204259). in International Application No. PCT/DK2009/000192. International Search Report issued on May 18, 2010 in application Preliminary Amendment filed Oct. 24, 2013 in U.S. Appl. No. No. PCT/DK2010/00019 (corresponding to US 8,603,526). 14/062,719. International Search Report issued on Jun. 2, 2010 in application No. Office Action issued Sep. 9, 2013 in U.S. Appl. No. 12/523,045. PCT/DK2010/050016 (corresponding to US 2010/203129). US 9,023,394 B2 Page 7

(56) References Cited Kais Group, “Hydrogentated Palm Kernel Oil.” http://kaisuroup.us/ our-products/palm-oil-products/hydrogentated-palm-kernel-oil. OTHER PUBLICATIONS Published 2011. Soy Info Center, "A Special Report on the History of Soy Oil, Soy International Search Report issued on Jan. 28, 2009 in application No. PCT/EP2008/056910 (corresponding to US 2010/239667). bean Meal & Modern Soy Protein Products.” http://soyinfocenter. MiraLAX(R), “MiraLAX(R) Drug Description.” Oct. 19, 2011. com/HSS hydrogenation2.php, published 2007. "Ascorbic acid.” Wikipedia, http://en.wikipedia.orq/wiki/Ascorbic Polysciences, Inc., “Monomers & Polymers.” http://www. acid, accessed Jan. 23, 2014. polysciences.com/Catalog/Department/Product/98/categorvid-298/ Wanka et al., “Phase Diagrams and Aggregation Behavior of productid 422/, published Apr. 3, 2004. Poly(oxyethylene)-Poly(oxypropylene)-Poly(oxyethylene) Triblock Copolymers in Aqueous Solutions.” vol. 27, pp. 4145-4159, 1994. * cited by examiner U.S. Patent May 5, 2015 Sheet 1 of 15 US 9,023,394 B2

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O 4 8. 2 16 20 24, 28 32 36 4 44 48 Fig. 14 US 9,023,394 B2 1. 2 FORMULATIONS AND METHODS FOR THE istrations. In certain Such embodiments, it has been found that CONTROLLED RELEASE OF ACTIVE DRUG relatively longer dosage forms are Suited to providing contin SUBSTANCES ued administration of at least one drug Substance over a relatively longer period of time, while relatively shorter dos RELATED APPLICATIONS age forms are useful for continued administration of at least one drug Substance over a shorter interval between adminis trations. This application is a continuation of U.S. patent applica In particular embodiments, the formulations described tion Ser. No. 127823,067, filed on Jun. 24, 2010, which claims hereinare provided as pharmaceutical compositions compris the benefit of U.S. Provisional Application No. 61/219,817, ing filed on Jun. 24, 2009. This application hereby incorporates 10 a) a matrix composition comprising by reference the U.S. priority applications enumerated i) an active drug Substance which may be any of the herein. active drug Substances described herein; and ii) at least one polyglycol, which may be any of the FIELD OF INVENTION polyglycols described herein; and 15 b) a coating as described herein having at least one opening Formulations and methods for the controlled release of exposing at least one Surface of said matrix, said coating active drug Substances are described herein. In certain being Substantially impermeable to an aqueous medium; embodiments, formulations and methods useful for once In some such embodiments, the matrix composition daily administration of active drug Substances are provided. included in the pharmaceutical composition has a cylindrical shape and, optionally, tapered end(s) (said cylindrical shape BACKGROUND OF INVENTION may be any of the shapes described herein), is formulated and configured at a length that facilitates controlled delivery of Many active drug Substances must be administered rela the active drug Substance over a desired dosing interval, and tively frequently in order to be functional over a longer time said matrix is Substantially surrounded by the coating, except 25 at the one or more openings. Pharmaceutical compositions period. Therefore controlled release formulations allowing according to Such embodiments may be formulated for con less frequent administration, but still having clinical efficacy tinued administration of the active drug Substance to an indi over the entire time interval between administrations, are vidual in need thereof over an interval of about 20 to 28 hours desirable. (e.g., a 24 hour interval). In one such embodiment, the com This is for example the case for analgesics for treating pain. position delivers clinically effective amounts of the active The pain relieving effect should be effective for the entire 30 drug substance to the individual over an interval of about 20 interval between individual administrations of the analgesic. to 28 hours (e.g., a 24 hour interval). Such compositions facilitate methods of continued administration of the active SUMMARY OF INVENTION drug Substance, wherein the composition is administered to the individual in need thereof at intervals ranging from about Controlled release formulations and methods for preparing 35 20 hours to 28 hours (e.g., a 24 hour interval). controlled release formulations for delivery of active drug In certain embodiments, the formulations described herein substances are described herein. The formulations described may be prepared as pharmaceutical compositions exhibiting herein may be employed to produce pharmaceutical compo particular pharmacological profiles. In certain embodiments, sitions, such as controlled release dosage forms, adjusted to a Such pharmaceutical compositions include a matrix compo specific administration scheme. In specific embodiments, the 40 sition as detailed herein. In embodiments of the pharmaceu formulations described herein provide controlled release of tical compositions formulated and produced to provide a one or more active drug Substances over a period of time particular pharmacological profile, such compositions may ranging from about 20 hours to about 28 hours. In certain Such be formulated and produced to provide, for example, a phar embodiments, the formulations provide controlled release of macological profile described in greater detail below. clinically effective amounts of one or more active drug Sub 45 Methods of treating an individual in need are also stances over a period of about 20 hours to 28 hours. Methods described herein. In certain embodiments, such methods for the controlled release of active drug Substances are also include providing a formulation according to the present provided herein. And in certain embodiments, such methods description and administering a clinically effective amount of include administering a controlled release formulation as such formulation to the individual. Moreover, in specific such described herein to an individual in need thereof. 50 embodiments, the formulation may be provided as a pharma In some embodiments the formulations described herein ceutical composition as detailed herein, including pharma are provided as pharmaceutical compositions, such as, for ceutical compositions including a matrix composition. In fur example, controlled release dosage forms, that provide con ther Such embodiments, the formulation may be produced and tinued administration of at least one active drug Substance administered in a manner that achieves a particular pharma over an interval of time of about 20 to 28 hours, and are 55 cological profile, as described herein. In specific embodi configured such that, when Such formulations are adminis ments, methods of treating an individual Suffering from pain tered to a subject at intervals ranging from about 20 to 28 are described. hours, the dosage form delivers the at least one drug Substance Administration of the formulations described herein may in an amount that remains clinically effective throughout the be carried out according to any of the methods described interval between administrations. 60 herein. Moreover, examples of individuals in need of the It has been found that the geometry of certain controlled formulations and methods provided herein are described in release formulations can be altered to obtain desired con greater detail below. trolled release characteristics, and in particular embodiments, it has been found that pharmaceutical compositions as DESCRIPTION OF DRAWINGS described herein of a certain length are useful for continued 65 administration of at least one active drug Substance over an FIG. 1 shows the mean hydrocodone plasma concentration interval ranging from about 20 to 28 hours between admin (pmol/L) versus time (h) curve after single dose administra US 9,023,394 B2 3 4 tion by dose group (0-42 h). Formulation A (6 mm) is treat FIG. 14 shows the mean morphine plasma concentration ment A, formulation A (7.5 mm) is treatment B, formulation (nmol/l) versus time curve by dose group (0–48 h). A (9 mm) is treatment C, formulation B (9 mm) is treatment D and Norco(R) is treatment E. DETAILED DESCRIPTION OF THE INVENTION FIG.2 shows the mean hydromorphone plasma concentra tion (pmol/L) versus time (h) curve after single dose admin Definitions istration by dose group (0-42 h). Formulation A (6 mm) is The term "cylindrical shape” as used herein refers to any treatment A, formulation A (7.5 mm) is treatment B, formu geometrical shape having the same cross section area lation A (9 mm) is treatment C, formulation B (9 mm) is throughout the length of the geometrical shape. The cross 10 section of a cylinder within the meaning of the present inven treatment D and Norco(R) is treatment E. tion may have any two dimensional shape, for example the FIG. 3 shows the mean norhydrocodone plasma concen cross section may be circular, oval, rectangular, triangular, tration (pmol/L) versus time (h) curve after single dose angular or star shaped. In specific embodiments, the pharma administration by dose group (0-42h). Formulation A (6 mm) ceutical compositions described herein have a cylindrical is treatment A, formulation A (7.5 mm) is treatment B, for 15 shape, wherein the end(s) are optionally tapered. mulation A (9 mm) is treatment C, formulation B (9 mm) is The term “cross section of the matrix’ is used to describe treatment D and Norco(R) is treatment E. the cross section of the pharmaceutical compositions FIG. 4 shows an estimated steady state hydrocodone curve, described herein, including matrix compositions, in the cylin plasma concentration (pmol/L) versus time (h). Formulation drical part of the pharmaceutical composition. Thus, in A (6 mm) is treatment A, formulation A (7.5 mm) is treatment embodiments, wherein the ends of the pharmaceutical com B, formulation A (9 mm) is treatment C, formulation B (9 position are tapered, the term “cross section of the matrix” mm) is treatment D and Norco(R) is treatment E. does not refer to the cross section of the tapered ends. FIG. 5 shows the mean oxycodone plasma concentration The terms “cross section area’’ or "cross sectional area’ (ng/mL) versus time (h) curve after single dose administra refer to the area of the cross section of the pharmaceutical tion by dose group (0–48 h). 6 mm is treatment A, 7.5 mm is 25 compositions described herein. Depending on the position treatment B, 9 mm is treatment Cand Oxycotin R) is treatment and shape of the openings of the coating, a specific area of the D. matrix included in the pharmaceutical composition is FIG. 6 shows the mean oxymorphone plasma concentra exposed to its Surroundings. In certain embodiments, at least tion (ng/mL) versus time (h) curve after single dose admin one opening that is essentially the same size and shape as the istration by dose group (0–48 h). 6 mm is treatment A, 7.5 mm 30 cross sectional area of the pharmaceutical composition is is treatment B, 9 mm is treatment C and OxycotinR) is treat provided in the coating. In some Such embodiments, the coat ment D. ing includes two openings that are essentially the same size FIG. 7 shows the mean noroxycodone plasma concentra and shape as the cross sectional area of the pharmaceutical tion (ng/mL) versus time (h) curve after single dose admin composition. istration by dose group (0–48 h). 6 mm is treatment A, 7.5 mm 35 The term “mean residence time' or MRT describes the is treatment B, 9 mm is treatment C and OxycotinR) is treat average time for all the drug molecules to reside in the body. ment D. MRT may be considered also as the mean transit time or mean FIG. 8 shows an estimated steady state oxycodone curve, Sojourn time. plasma concentration (ng/mL) versus time (h). 6 mm is treat MRT is calculated as AUMCo/AUCo., where ment A, 7.5 mm is treatment B, 9 mm is treatment C and 40 AUMCo. is the area under the first moment curve from time OxycotinR) is treatment D. zero to infinity. AUMCo., AUMCo.--tC/K+C/(K). FIG. 9 shows the relationship between release times (% The term “steady state' refers to the state when the plasma drug release versus time (minutes)) in vitro for a pharmaceu concentration level of an active drug Substance following one tical composition according to the present description con dosing is the same within the standard deviation as the plasma taining oxycodone 40 mg versus tablet length 6, 7.5 and 9 45 concentration level following the next dosing. Thus, for phar . maceutical compositions for once daily administration then at FIG. 10 shows in vitro dissolution results (drug release (%) steady state AUCo-24, AUCo-2a+/- the standard Versus time (minutes)) of pharmaceutical composition A (30 deviation, and Co-24, Co-24) +/- the standard mg morphine), B1 (30, 60, 100 and 200 mg morphine) and B2 deviation, where “h” is hours and “d' is day. (100 mg morphine) according to the present description. 50 The term “substantially impermeable' as used herein FIG. 11 shows examples of geometries of pharmaceutical refers to a material, for example, a coating, that is imperme compositions according to the present description. The active able to aqueous medium for at least 24 hours. Therefore, in drug Substance is dispersed in a matrix partly covered by a certain embodiments, a Substantially impermeable coating as coating, preferably a non-impermeable coating. I: 3-D view described herein in association with a pharmaceutical com of roundtablet and a tablet with one tapered end. II: 3-D view 55 position is impermeable to aqueous medium for at least 24 of one type of oval tablet and matrix with different shapes. III: hours. In some Such embodiments, the Substantially imper 3-D view of second type of oval tablet with round matrix. IV: meable coating is impermeable to aqueous medium for at 3-D view of third type of oval tablet with an oval matrix. least 48 hours. Relative sizes of tablets are not shown. The term “trough' is defined as the average plasma con FIG. 12 shows the relationship between release times (% 60 centration in a steady state individual just prior to the follow drug release versus time (minutes)) in vitro for a pharmaceu ing dose. Thus, for pharmaceutical compositions prepared for tical composition according to the present description con continued administration of an active drug Substance at inter taining hydrocodone versus tablet length 6 mm (medium vals of about 20 to 28 hours (e.g., a 24 hour interval) between load), 7.5 mm (medium load), 9 mm (medium load) and 9 mm individual administrations, the trough is the average plasma (high load). 65 concentration in a steady state individual 20 to 28 hours (e.g., FIG. 13 shows the mean steady state morphine plasma a 24 hour interval) after dosing and just prior to the following concentration (nmol/l) versus time curve (0-24 h). dose. A steady state simulation may be calculated based on US 9,023,394 B2 5 6 measurement of active drug Substance or metabolites in active drug substance from 0-12 hafter administration of said serum after a single dose administration and based on Such a active drug substance. AUC, is the average area under the simulation a theoretical trough may be determined. As exem curve of a plasma concentration profile of an active drug plified herein, the trough may be determined as an average of substance from 0-24 h after administration of said active drug the trough in at least 5 different individuals. 5 Substance. AUCoast, is the average area under the curve of a The term “C” is defined by the average lowest plasma plasma concentration profile of an active drug Substance from concentration observed overa dosing interval. Thus, for phar 0–48 h after administration of said active drug substance. maceutical compositions prepared for continued administra AUCo., is obtained from Sum of steady state AUCs (I.e. tion over an interval of about 20 to 28 hours between indi X(AUCAUC, . . . AUC)) between measurements vidual administrations, the C is defined by the average 10 from each sample point. The AUCs are calculated by the lowest plasma concentration observed over the dosing-inter linear trapezoidal method. If the last blood sample is taken at val of about 20 to 28 hours (e.g., a 24 hour interval). As less than Xh, for example, less than 24 h after drug adminis exemplified herein, C may be determined as an average of tration, the Xh value, such as the 24 h value will be extrapo C, in at least 5 different individuals. lated using the terminal elimination rate constant as described The term 'steady state C is defined as the average 15 below. Single missing values will remain missing, i.e. corre plasma concentration of an active drug Substance in a steady sponding to interpolation between the neighbouring points state individual observed 24 hours after last administration of when calculating AUC. Similarly AUCx-y indicates the area said active drug Substance. A steady state simulation may be under the curve of a plasma concentration profile of an active calculated based on measurement of active drug Substance or drug Substance from X to y after administration of said active metabolites in serum after a single dose administration and drug Substance calculated in a similar manner. based on such a simulation a theoretical C may be deter The term “protraction index' as used herein illustrates the mined. As exemplified herein, 'steady state C may be flatness of the steady state plasma concentration profile and is determined as an average of “steady state C in at least 5 defined as the average concentration in the 24 hour dosing different individuals. interval divided by the maximum concentration, i.e. The term "steady state C is the average highest plasma 25 ((AUCo/24 h)/C). In the theoretical case where the concentration at Steady state observed over the dosing inter profile is completely flat the average concentration will be val. Thus, for pharmaceutical compositions for continued identical to the maximum concentration and the protraction administration of an active drug Substance over an interval of index will be equal to 1. Hence, due to the fact that the average about 20 to about 28 hours (e.g., a 24 hour interval) between concentration cannot take a value higher than the maximum individual administrations, C is defined by the highest 30 concentration, the protraction index can never be higher than plasma concentration at steady state observed over the dos 1. In cases where the profile is substantially flat, the difference ing-interval. C may also be referred to as "peak plasma between the maximum concentration and the average con concentration. A steady state simulation may be calculated centration is Small and the protraction index will take a value based on measurement of active drug Substance or metabo close to 1. In other cases where the maximum concentration lites in serum after a single dose administration and based on 35 for instance is 5 times higher than the average concentration Such a simulation, a theoretical steady state C may be the protraction index will take the value 0.2. determined. As exemplified herein, “steady state C may Polyglycol be determined as an average of 'steady state C in at least The formulations described herein are prepared as phar 5 different individuals. maceutical compositions and, in specific embodiments, the The term “steady state individual' refers to an individual to 40 pharmaceutical compositions described herein include a whom the pharmaceutical compositions described herein matrix composition comprising at least one polyglycol. have been administered for a sufficient number of times in A matrix composition as described herein may comprise order to have arrived at steady state. Thus, for pharmaceutical more than one different kind of polyglycol. Such as 2, for compositions prepared for administration once daily, a steady example 3. Such as 4, for example 5. Such as more than 5 state individual is an individual to whom a pharmaceutical 45 different polyglycols. In certain such embodiments, the composition according to the present description has been matrix composition comprises 1 to 4 different polyglycols. In administered once daily for a sufficient number of days in one such embodiment, the matrix composition comprises 1 to order to have arrived at steady state. Steady state is reached 3 different polyglycols. In another such embodiment, the when the plasma concentration level after one dosing is the matrix composition comprises 2 different polyglycols. same within the standard deviation as the plasma concentra 50 The polyglycol materials included in the pharmaceutical tion level after the next dosing, meaning for once daily dosing compositions described herein may, for example, be in the that AUCo-24). AUCo-24, 41, and Cnaeco-24n). form of a homopolymer and/or a copolymer. If the matrix Co-24 where “h” is hours and "d" is day. In certain composition comprises more than one polyglycol they may embodiments, as described herein, a steady state individual, all be different homopolymer, or different copolymers or a is an individual to whom the pharmaceutical compositions 55 mixture of homopolymers and copolymers. In one embodi according to the present invention has been administered ment, the matrix composition comprises at least one polyg once daily for a period of time selected from, for example, at lycol, which is a homopolymer and at least one polyglycol, least 3 days, at least 4 days, and at least 7 days. which is a copolymer. In another embodiment, the matrix The term “T” refers to the average time lapsing between composition comprises at least one polyglycol, which is a administration of a pharmaceutical composition and arrival at 60 homopolymer. C. As exemplified herein, T. may be determined as an The polyglycols included in the matrix compositions average of T in at least 5 different individuals. described herein may be selected from substantially water AUC is defined by the average area under the curve of a soluble, thermoplastic, crystalline, semi-crystalline or amor plasma concentration profile of an active drug Substance from phous or a mixture of substantially water soluble, crystalline, 0-Xhafter administration of said active drug Substance, where 65 semi-crystalline or amorphous polymers. In particular, in cer “h” is hours. Thus, where “x'=12, the AUC, is the average tain embodiments, the polyglycol is at least thermoplastic. area under the curve of a plasma concentration profile of an Suitable polyglycols for use in a matrix composition accord US 9,023,394 B2 7 8 ing to the present description include, for example, polyeth weight of in the range of approximately 50,000 to 500,000 ylene glycols, as well as derivatives of polyethylene glycol, daltons. In certain such embodiments the average molecular Such as mono or dimethoxypolyethylene glycols (mPEGs), weight of the PEO may be selected from, for example, polyethylene oxides and/or block copolymers of ethylene approximately 100,000 to 400,000 daltons, approximately oxide and propylene oxide. 200,000 to 300,000 daltons, approximately 150,000 to 250, Polyethylene glycols (PEGs) are linear polydisperse poly 000 daltons, and approximately 200,000 daltons. This is in mers composed of repeating units of ethylene glycol. Their particular the case for pharmaceutical compositions, wherein chemical formula is HOCHICHOCHCH-OH, where m the matrix has a length in a range selected from 7.5 to 15 mm, represents the average number of repeating units. Alterna 8 to 15 mm, and 8 to 11 mm, and wherein said pharmaceutical tively, the general formula HOCH2CHI.OH may be used to 10 composition is formulated for continued administration of an represent polyethylene glycol, where n is as number m in the active drug substance for an interval of about 20 to about 28 previous formula--1. See the structural presentations of poly hours between individual administrations. ethylene glycol below, wherein n is the average number of In another embodiment of the invention the matrix com oxyethylene groups, n equals m+1. prises only one polyethylene oxide, preferably a PEO with an 15 average molecular weight of in the range of 100,000 to 500, 000 daltons, for example in the range of 200,000 to 400,000 daltons, such as in the range of 250,000 to 350,000 daltons, for example approximately 300,000 daltons, such as 300,000 "N-r--" H --N-1 on daltons. This is in particular the case for pharmaceutical com positions according to the invention, wherein the matrix has a In specific embodiments, the matrix composition com length of in the range of 7.5 to 15 mm, preferably a length of prises at least one polyglycol which is a polyethylene oxide. in the range of 7.5 to 10 mm, Such as a length in the range of Polyethylene oxides (PEOs) are linear polydisperse nonionic 7.5 to 8 mm, wherein said pharmaceutical composition is polymers composed of repeating units of ethylene oxide. formulated for continued administration within the range of Their chemical formula is HOCH2CH2OH, where n rep 25 20 to 28 hours interval between individual administrations. resents the average number of oxyethylene groups. See the In a specific embodiment, at least one polyglycol is a structural presentation of polyethylene oxide below, wherein polyethylene oxide or a polyethylene glycol that has a n is the average number of oxyethylene groups. Depending on molecular weight selected from approximately 20,000 dal preparation method high molecular weight PEO may have tons, approximately 35,000 daltons, approximately 50,000 one terminal methyl group. 30 daltons, approximately 100,000 daltons, approximately 200, 000 daltons, approximately 300,000 daltons, and approxi mately 400,000 daltons. In the present context "approxi mately” means +/-30%. PEG is commercially available with average molecular weights up to 35,000 daltons. PEO is -N-Sh 35 commercially available with average molecular weights up to 8,000,000 daltons. In specific embodiments, the polymer is a In general PEG refers to polymer chains with molecular PEO having an average molecular weight of at least 100,000 weights below 20,000 daltons, while PEO refers to higher daltons, such as in the range of 100,000 to 8,000,000 daltons, molecular weights polymers. However, because of the simi for example in the range of 100,000 to 7,000,000 daltons, larities between PEO and PEG, the terms are often used 40 such as in the range of 100,000 to 5,000,000 daltons, for interchangeably for the same compound. example in the range of 100,000 to 4,000,000 daltons, such as Polyethylene glycols and/or polyethylene oxides, which in the range of 100,000 to 2,000,000 daltons, for example in are Suitable for use in the matrix composition are those having the range of 100,000 to 1,000,000 daltons, such as in the range an average molecular weight of at least 20,000 daltons, such of 100,000 to 900,000 daltons. When PEO is employed with as an average molecular weight of in the range of 20,000 to 45 a molecular weight in the lower end, the PEO typically has a 700,000 daltons, for example in the range of 20,000 to 600, molecular weight as mentioned in the preceding paragraph. 000 daltons, such as in the range of 35,000 to 500,000 daltons, Commercially available PEOs with a molecular weight in the for example in the range of 35,000 to 400,000 daltons, such as higher end typically exhibit a molecular weight selected from in the range of 35,000 to 350,000 daltons, for example in the approximately 900,000 daltons, approximately 1,000,000 range of 50,000 to 350,000 daltons, such as in the range of 50 daltons, approximately 2,000,000 daltons, approximately 100,000 to 300,000 daltons, for example in the range of 4,000,000 daltons, approximately 5,000,000 daltons, 150,000 to 350,000 daltons, such as in the range of 200,000 to approximately 7,000,000 daltons, and approximately 8,000, 300,000 daltons. In certain embodiments, polyethylene gly 000 daltons. cols and/or polyethylene oxides suitable for use in the matrix A matrix composition as described herein may also com compositions described herein are those having an average 55 prise at least one polyglycol which is a copolymer. molecular weight selected from approximately 35,000 dal In some embodiments, the matrix composition comprises tons, approximately 50,000 daltons, approximately 75,000 at least one polyglycol which is a poloxamer. Poloxamers are daltons, approximately 100,000 daltons, approximately 150, copolymers or block copolymers and are a range of non-ionic 000 daltons, approximately 200,000 daltons, approximately surfactants of polyethylene glycol (PEG) and polypropylene 250,000 daltons, approximately 300,000 daltons, approxi 60 glycol (PPG). mately 400,000 daltons, 150,000 daltons, 200,000 daltons, The poloxamer may be Diol EO/PO block copolymers, 250,000 daltons, 300,000 daltons, 400,000 daltons. In the which for example in chemical abstracts are described under present context, referring to the molecular weight of polyeth the Scientific name -hydroxy-hydroxypoly(oxyethylene)poly ylene glycols and polyethylene oxides, “approximately (oxypropylene)-poly(Oxyethylene)-block copolymer in com means +/-30%. 65 bination with the CAS register number. In specific embodi In one embodiment, the matrix comprises only one poly ments, a suitable poloxamer for use in a composition of the ethylene oxide, such as a PEO with an average molecular invention has a HLB value of at least about 18 such as, for US 9,023,394 B2 9 10 example, at least approximately 20, preferably at least 24. The to be used. Thus, in particular embodiments, the average molecular weight of a Suitable poloxamer is typically polyglycol(s) employed in the matrix compositions described at least about 2,000 daltons. herein will suitably have a melting point of in the range of 38° Block copolymers of ethylene oxide and propylene oxide C.-120° C., such as in the range of 38° C. to 100° C., for that may be included in the matrix compositions described 5 example in the range of 40°C. to 80° C. herein have a molecular weight of at least 2,000 daltons, In a specific embodiment, the matrix composition com typically in the range of 3,000 to 30,000 daltons, such as in the prises at least one polyethylene oxide and at least one copoly range of 4,000 to 15,000 daltons. C. Exemplary poloxamers that may be used in the matrix In addition to a polymer of a polyglycol type, the matrix compositions according to the present description have the 10 composition may comprise an additional polymer, Such as, formula HO(CHO) (CHO), (CHO)H, where “a” is an for example, at least one polymer selected from: modified or integer from 10 to 150, such as from 30 to 140, for example unmodified water soluble natural polymers such as gluco from 50 to 100, such as from 65 to 90, for example from 70 to mannan, galactan, glucan, polygalacturonic acid, polyxylane, 90, and “b' is an integer from 10 to 80, such as from 15 to 80, polygalactomannans, rhanogalacturonan, polyxyloglycan, for example from 20 to 60, such as from 25 to 55. 15 arabinogalactan, and starch, cellulose, chitosan, alginate, In one embodiment, the matrix comprises one or more fibrin, collagen, gelatin, hyaluronic acid, amylopectin, pectin copolymers, preferably one or more copolymers selected including low methylated or methoxylated pectins, dextran from the group consisting of poloxamers, such as poloxamer and fatty acids and alcohols; synthetic polymers such as poly 188 and/or poloxamer 407. This is in particular the case for vinylpyrrolidone (PVP), PVA, PVB, Eudragit L methyl ester, pharmaceutical compositions described herein, wherein the Eudragit L., Eudragit RL, Eudragit RS, Eudragit E, Eudragit matrix has a length in a range selected from 7.5 to 15 mm and S. PHPV. PHA, PCL, PLGA and PLA; and hydrogels made 8 to 10 mm, wherein said pharmaceutical composition is from the polymers or combined polymers mentioned above formulated for continued administration of an active drug and or from polymers originated from HEMA, HEEMA, substance over an interval of about 20 to about 28 hours MEMA, MEEMA, EDGMA, NVP, VAc, AA, acrylamide, between individual administrations. 25 MAA, HPMA, PEGA, PEGMA, PEGDMA, PEGDA, and In a specific embodiment, the matrix comprises at least two PEGDMA. different copolymers selected from poloxamers, such as One or more polymers are typically present in a matrix poloxamer 188 and poloxamer 407. In certain such embodi composition described herein in an amount of from 5 to ments, the pharmaceutical compositions include a matrix 99.9% w/w, such as from 5 to 95% w/w, such as from 5 to 80% having a length in a range selected from a range of 8 to 15 mm 30 wfw, such as from 10 to 80% w/w, such as from 20 to 80% and a range of 8 to 10 mm, and said pharmaceutical compo w/w, for example from 30 to 80% w/w, such as from 40 to sition is formulated for continued administration of an active 80% w/w, for example from 45 to 75% w/w. drug substance over and interval of about 20 to 28 hours In Some embodiments, the total concentration of the polyg between individual administrations. lycols (notably the sum of homo- and copolymers of the In another specific embodiment, the matrix comprises a 35 polyglycol type) in the matrix composition may be from 5 to single poloxamer, Such as poloxamer 188. In certain Such 99% w/w, such as from 15 to 95% w/w, for example from 30 embodiments, the pharmaceutical compositions include a to 90% w/w, such as from 30 to 85% w/w, for example from matrix having a length in a range selected from a range of 7.5 30 to 80% w/w, such as from 40 to 80% w/w, for example to 15 mm and a range of 7.5 to 10 mm, and said pharmaceu from 45 to 75% w/w, such as from 40 to 50% w/w, for tical composition is formulated for continued administration 40 example from 45 to 50% w/w, such as from 60 to 85% w/w, of an active drug substance over and interval of about 20 to 28 for example from 60 to 80% w/w, for example from 70 to 75% hours between individual administrations. w/w, such as from 71 to 75% w/w. The matrix compositions described herein may comprise In some embodiments, the concentration of the polyglycol mixtures of PEO with different average molecular weights, homopolymer in the matrix composition may be from 5 to for example, in order to obtain a PEO with a desirable average 45 80% w/w, and in those cases where the homopolymer is the molecular weight. The same applies to PEG. only thermoplastic polymer present in the matrix composi Thus, in some embodiments, the matrix comprises two tion, then the concentration may be from 20 to 80 w/w, such different PEO materials with different average molecular as from 40 to about 80% w/w, such as for example from 70 to weights. In one such embodiment, a first PEO material may 80% w/w, such as from 70 to 75% w/w, for example from exhibit an average molecular weight in a range selected from 50 about 71 to about 75% w/w. approximately 150,000 to approximately 250,000 daltons, In certain embodiments, the concentration of the and approximately 200,000 daltons, while the second PEO homopolymers in the matrix composition is in the range of 5 material may exhibit an average molecular weight selected to 90% w/w, such as in the range of 20 to 85% w/w, for from approximately 250,000 to approximately 350,000 dal example in the range of 20 to 75% w/w, such as in the range tons, approximately 200,000 to approximately 300,000 dal 55 of 20 to 70% w/w for example in the range of 20 to 40% w/w, tons and approximately 300,000 daltons. In certain such such as in the range of 30 to 85% w/w, for example in the embodiments, the pharmaceutical compositions include a range of about 30 to 75% w/w, such as in the range of 30 to matrix having a length in a range selected from a range of 7.5 60% w/w, for example in the range of 30 to 40% w/w, such as to 15 mm and a range of 8 to 10 mm, and said pharmaceutical in the range of 30 to 35% w/w, such as in the range of 31 to composition is formulated for continued administration of an 60 about 33% w/w, such as in the range of 50 to 85% w/w, from active drug substance over an interval of about 20 to 28 hours 60 to 80% w/w, for example in the range of 70 to 80% w/w, for between individual administrations. example in the range of 70 to 75% w/w, such as in the range It should be noted that, in this context, Vitamin E polyeth of 71 to about 73% w/w. ylene glycol Succinate (TPGS) is not considered a polyglycol. The concentration of the polyglycol copolymer in the The polyglycol used in the compositions described herein 65 matrix composition, if present in combination with a polyg should have a melting point higher than the body temperature lycol homopolymer, may be in the range of 0 to 60% w/w, of the individual (e.g., a human) in which the composition is such as for example 0 to 30% w/w. If the copolymer is the sole US 9,023,394 B2 11 12 thermoplastic polymer in the matrix composition, the con Hexobarbital. Thiopental, Narcobarbital, Opioid anaesthet centration may be from about 5 to about 99.5% w/w such as ics, Fentanyl, Alfentanil, Sufentanil, Phenoperidine, Anileri those ranges described above and described for the dine, Remifentanil, Other general anaesthetics, Droperidol, homopolymer. Ketamine, Propanidid, Alfaxalone, Etomidate, Propofol, In some embodiments, the concentration of polyglycols Hydroxybutyric acid, Nitrous oxide, Esketamine, Xenon, which are co-polymers in the matrix composition is in the Esters of aminobenzoic acid, Metabutethamine, Procaine, range of 0 to 30% w/w, such as in the range of 1 to 20% w/w, Tetracaine, Chloroprocaine, Benzocaine, Amides, Bupiv for example in the range of 2 to 10% w/w, such as in the range acaine, Lidocaine, Mepivacaine, Prilocaine. Butanilicaine, of 2 to 5% w/w, such as in the range of 5 to 30% w/w, for Cinchocaine, Etidocaine, Articaine, Ropivacaine, Levobupi example in the range of 5 to 20% w/w, for example in the 10 vacaine, Esters of benzoic acid, Cocaine. Other local anaes range of 5 to 15% w/w, such as less than 15% w/w, for thetics, Ethyl chloride, Dyclonine, Phenol, Capsaicin; example less than 10% w/w, such as less than 5% w/w, such Antimigraine active Substances, such as, for example: as less than 1% w/w, for example 0% w/w. Ergot alkaloids, Dihydroergotamine, Ergotamine, Methyser Active Drug Substance gide, Lisuride, Corticosteroid derivatives, Flumedroxone, An active drug Substance Suitable for use in the formula 15 Selective serotonin (5HT1) agonists, Sumatriptan, Naratrip tions and methods described herein is a therapeutically, pro tan, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan, Fro phylactically and/or diagnostically active drug Substance Vatriptan, Other antimigraine preparations, Pizotifen, Cloni (herein also abbreviated “active drug substance'). dine, 1prazochrome, Dimetotiazine, Oxetorone; Examples of specific active drug Substances suitable for Antiepileptic active Substances. Such as, for example:Bar use in the compositions and methods provided herein include: biturates and derivatives, Methylphenobarbital, Phenobar Anti-inflammatory and antirheumatic active Substances, bital, Primidone, Barbexaclone, Metharbital, Hydantoin such as, for example: Butylpyrazolidines, Phenylbutazone, derivatives, Ethotoin, Phenytoin, Amino(diphenylhydantoin) Mofebutazone, Oxyphenbutazone, ClofeZone, KebuZone, Valeric acid, Mephenytoin, Fosphenytoin, Oxazolidine Acetic acid derivatives and related Substances, Indometacin, derivatives, Paramethadione, Trimethadione, Ethadione, Sulindac, Tolimetin, Zomepirac, Diclofenac, Alclofenac, 25 Succinimide derivatives, Ethosuximide, Phensuximide, Bumadizone, Etodolac, Lonazolac, Fentiazac, Acemetacin, Mesuximide, Benzodiazepine derivatives, Clonazepam, Car Difempiramide, Oxametacin, Proglumetacin, Ketorolac, Ace boxamide derivatives, Carbamazepine, Oxcarbazepine, Rufi clofenac, BufeXamac. Oxicams, Piroxicam, Tenoxicam, namide, Fatty acid derivatives, Valproic acid, Valpromide, Droxicam, Lornoxicam, Meloxicam, Methotrexate, Propi Aminobutyric acid, Vigabatrin, Progabide, Tiagabine. Other onic acid derivatives, Ibuprofen, Naproxen, Ketoprofen, 30 antiepileptics, Sultiame, Phenacemide, Lamotrigine, Fel Fenoprofen, Fenbufen, Benoxaprofen, Suprofen, Pirprofen, bamate, Topiramate, Gabapentin, Pheneturide, Levetirac Flurbiprofen, Indoprofen, Tiaprofenic acid, Oxaprozin, Ibu etam, Zonisamide, Pregabalin, Stiripentol, Lacosamide, Bec proxam, Dexibuprofen, Flunoxaprofen, Alminoprofen, lamide; Dexketoprofen, Fenamates, Mefenamic acid, Tolfenamic Anticholinergic active substances, such as, for example: acid, Flufenamic acid, Meclofenamic acid, Coxibs, Cele 35 Tertiary amines, Trihexyphenidyl, Biperiden, Metixene, Pro coxib, Rofecoxib, Valdecoxib, Parecoxib, Etoricoxib, cyclidine, Profenamine, Dexetimide, Phenglutarimide, Lumiracoxib, Nabumetone, Niflumic acid, AZapropaZone, Mazaticol, Bornaprine, Tropatepine, Ethers chemically close Glucosamine, BenZydamine, Glucosaminoglycan polysul to antihistamines, Etanautine, Orphenadrine (chloride), fate, ProquaZone, Orgotein, Nimesulide, Feprazone, Ethers of tropine or tropine derivatives, BenZatropine. Ety Diacerein, Morniflumate, Tenidap, Oxaceprol, Chondroitin 40 benZatropine; Sulfate, Feprazone, Dipyrocetyl, Acetylsalicylic acid, Quino Dopaminergic active Substances, such as, for example: lines, Oxycinchophen, Gold preparations, Sodium aurothi Dopa and dopa derivatives, Levodopa, Melevodopa, Eti omalate, Sodium aurotiosulfate, Auranofin, Aurothioglucose, levodopa, Adamantane derivatives, Amantadine, Dopamine Aurotioprol, Penicillamine and Bucillamine: agonists, Bromocriptine, Pergolide, Dihydroergocryptine Analgesics. Such as, for example: Opioids, Natural opium 45 mesylate, Ropinirole, Pramipexole, Cabergoline, Apomor alkaloids, Morphine, Opium, Hydromorphone, Nicomor phine, Piribedil, Rotigotine, Monoamine, oxidase B inhibi phine, Oxycodone, Dihydrocodeine, Diamorphine, Papav tors, Selegiline, Rasagiline. Other dopaminergic agents, Tol eretum, Codeine, Phenylpiperidine derivatives, Ketobemi capone, Entacapone, Budipine; done, Pethidine, Fentanyl, Diphenylpropylamine derivatives, Antipsychotic active Substances, such as, for example: Dextromoramide, Piritramide, Dextropropoxyphene, Bezit 50 Phenothiazines with aliphatic side-chain, Chlorpromazine, ramide, Methadone, Benzomorphan derivatives, Pentazo Levomepromazine, Promazine, Acepromazine, Triflupro cine, Phenazocine, Oripavine derivatives, Buprenorphine, mazine, Cyamemazine, Chlorproethazine, Phenothiazines Morphinan derivatives, Butorphanol, Nalbuphine, Tilidine, with piperazine structure, Dixyrazine, Fluphenazine, Per Tramadol, Dezocine, Salicylic acid and derivatives, Acetyl phenazine, Prochlorperazine. Thiopropazate, Trifluopera salicylic acid, Aloxiprin, Choline Salicylate, Sodium salicy 55 Zine, Acetophenazine. Thioproperazine, Butaperazine, Pera late, Salicylamide, Salsalate, Ethenzamide, Morpholine sali zine, Phenothiazines with piperidine structure, Periciazine, cylate, Dipyrocetyl, Benorilate. Diflunisal, Potassium Thioridazine, Mesoridazine, Pipotiazine, Butyrophenone salicylate, Guacetisal, Carbasalate calcium, Imidazole sali derivatives, Haloperidol, Trifluperidol, Melperone, Moper cylate, Pyrazolones, Phenazone, Metamizole sodium, Ami one, Pipamperone, Bromperidol, Benperidol, Droperidol, nophenaZone, PropyphenaZone, NifenaZone, Anilides, 60 Fluanisone, Indole derivatives, Oxypertine, Molindone, Paracetamol, Phenacetin, Bucetin, Propacetamol. Other anal Sertindole, Ziprasidone. Thioxanthene derivatives, Flupen gesics and antipyretics, Rimazolium, Glafenine, Floctafe tixol, Clopenthixol, Chlorprothixene, Tiotixene, Zuclo nine, Viminol, Nefopam, Flupirtine, Ziconotide; penthixol, Diphenylbutylpiperidine derivatives, Fluspirilene, Anesthetics, such as, for example: Ethers, Diethyl ether, Pimozide, Penfluridol, Diazepines, oxazepines and thiaz Vinyl ether, Halogenated hydrocarbons, Halothane, Chloro 65 epines, Loxapine, Clozapine, Olanzapine, Quetiapine, Neu form, Methoxyflurane, Enflurane, Trichloroethylene, Isoflu roleptics, in tardive dyskinesia, Tetrabenazine, BenZamides, rane, Desflurane, Sevoflurane, Barbiturates, Methohexital, Sulpiride, Sultopride, Tiapride, Remoxipride, Amisulpride, US 9,023,394 B2 13 14 Veralipride, Levosulpiride, Lithium, Other antipsychotics, Stigmine, Pyridostigmine, Distigmine, Ambenonium, Cho Prothipendyl, Risperidone, Clotiapine. Mosapramine, line esters, Carbachol, Bethanechol, Other parasympathomi Zotepine, Aripiprazole, Paliperidone; metics, Pilocarpine, Choline alfoscerate; Anxiolytic active Substances. Such as, for example: Ben Active Substances used in addictive disorders, such as, for Zodiazepine derivatives, Diazepam, Chlordiazepoxide, example: Nicotine, Bupropion, Varenicline, Disulfiram, Cal Medazepam, Oxazepam, Potassium cloraZepate, Lorazepam, cium carbimide, Acamprosate, Naltrexone, Buprenorphine, Adinazolam, Bromazepam, Clobazam, Ketazolam, Methadone, Levacetylmethadol, Lofexidine, Betahistine, Prazepam, Alprazolam, Halazepam, Pinazepam, Cinnarizine, Flunarizine, Acetylleucine, Gangliosides and Camazepam, Nordazepam, Fludiazepam, Ethyl loflazepate, ganglioside derivatives, Tirilazad, Riluzole, Xaliproden, Etizolam, Clotiazepam, Cloxazolam, Tofisopam, Diphenyl 10 Hydroxybutyric acid, Amifampiridine; and methane derivatives, Hydroxyzine, Captodiame, Carbam Opium alkaloids and derivatives, such as, for example: ates, Meprobamate, Emylcamate, Mebutamate, Dibenzo-bi Ethylmorphine, Hydrocodone, Codeine, Opium alkaloids cyclo-octadiene derivatives, BenZoctamine, with morphine, Normethadone, Noscapine, Pholcodine, AZaspirodecanedione derivatives, Buspirone. Other anxiolyt Dextromethorphan, Thebacon, Dimemorfan, Acetyldihydro ics, Mephenoxalone, Gedocarnil, Etifoxine; 15 codeine, BenZonatate, Benproperine, Clobutinol, Isoaminile, Hypnotic and sedative active Substances, such as, for Pentoxyverine, Oxolamine, Oxeladin, Clo?edanol, example: Barbiturates, Pentobarbital. Amobarbital, Butobar Pipazetate, Bibenzonium bromide, Butamirate, Fedrilate, bital, Barbital, Aprobarbital, Secobarbital, Talbutal, Vinyl Zipeprol, Dibunate, Droxypropine, Prenoxdiazine, Dro bital, Vinbarbital, Cyclobarbital, Heptabarbital, Reposal, propizine, Cloperastine, Meprotixol, Piperidione, Tipepi Methohexital, Hexobarbital. Thiopental, Etallobarbital, Allo dine, Morclofone, Nepinalone, Levodropropizine, barbital, Proxibarbal, Aldehydes and derivatives, Chloral Dimethoxanate. hydrate, Chloralodol, Acetylglycinamide chloral hydrate, In certain embodiments, the active drug Substance may, for Dichloralphenazone, Paraldehyde, Benzodiazepineemepro example, bean active drug Substance with abuse potential that nium derivatives, Flurazepam, Nitrazepam, Flumitrazepam, presents a safety risk. Such active drug Substance may, for Estazolam, Triazolam, Lorimetazepam, Temazepam, Mida 25 example, be selected from: Zolam, Brotizolam, Quazepam, Loprazolam, Doxefazepam, 1-(1-Phenylcyclohexyl)pyrrolidine, 1-(2-Phenylethyl)-4- Cinolazepam, Piperidinedione derivatives, Glutethimide, phenyl-4-acetoxypiperidine, 1-1-(2-Thienyl)-cyclohexyl Methyprylon, Pyrithyldione, Benzodiazepine related drugs, piperidine, 1-1-(2-Thienyl)cyclohexylpyrrolidine, 1-Me Zopiclone, Zolpidem, Zaleplon, Ramelteon. Other hypnotics thyl-4-phenyl-4-propionoxy-piperidine, and sedatives, Methaqualone, Clomethiazole, Bromisoval, 30 1-Phenylcyclohexylamine, 1-Piperidinocyclohexanecarbo Carbromal, Scopolamine, Propiomazine, Triclofos, Ethchlo nitrile, 2,5-Dimethoxy-4-ethylamphetamine, 2.5- rvynol, Valerian, Hexapropymate, Bromides, Apronal, Val Dimethoxyamphetamine, 2C-B-(4-bromo-2,5-dimethox noctamide, Methylpentynol, Niaprazine, Melatonin, Dexme ypenethylamine), 2C-D (2,5-dimethoxy-4- detomidine, Dipiperonylaminoethanol; methylphenethylamine), 2C-I (4-iodo-2,5-dimethoxy Antidepressant active Substances, such as, for example: 35 phenethylamine), 2C-T-2 (2,5-dimethoxy-4- Non-selective monoamine reuptake inhibitors, Desipramine, ethylthiophenethylamine), 2C-T-4 (2,5-dimethoxy-4- Imipramine, Imipramine oxide, Clomipramine, Opipramol. isopropyl thiophenethylamine), 2C-T-7 (2,5-dimethoxy-4- Trimipramine, Lofepramine, Dibenzepin, Amitriptyline, (n)-propylthiopenethylamine), 3.4-Methylene Nortriptyline, Protriptyline, Doxepin, Iprindole, Melitracen, dioxymethamphetamine, 3,4,5-Trimethoxyamphetamine, Butriptyline, DoSulepin, Amoxapine, Dimetacrine, Aminep 40 3.4-Methylenedioxyamphetamine, 3.4-Methylenedioxy-N- tine, Maprotiline, Quinupramine, Selective serotonin ethylamphetamine, 3-Methylfentanyl. 3-Methylthiofentanyl, reuptake inhibitors, Zimeldine, Fluoxetine, Citalopram, Par 4-Brorno-2,5-dimethoxyamphetamine, 4-Bromo-2,5- oxetine, Sertraline, Alaproclate, Fluvoxamine, Etoperidone, dimethoxyphenethylamine, 4-Methoxyamphetamine, 4-Me Escitalopram, Monoamine oxidase inhibitors, non-selective, thyl-2,5-dimethoxyamphetamine, 4-Methylaminorex (cis Isocarboxazid, Nialamide, Phenelzine, Tranylcypromine, 45 isomer), 5-MeO-DIPT (5-Methoxy-N,N-diisopropyl Iproniazide, proclozide, Monoamine oxidase A inhibitors, tryptamine), 5-MeO-DMT (5-Methoxy-N,N-dimethyl Moclobemide, Toloxatone. Other antidepressants, Oxitrip tryptamine). 5-Methoxy-3,4-methylenedioxyamphetamine, tan, Tryptophan, Mianserin, Nomifensine, Trazodone, Nefa Acetorphin, Acetorphine, Acetyl-alpha-methylfentanyl. Zodone, Minaprine, Bifemelane, Viloxazine, Oxaflozane, Acetyl-alpha-methylfentanyl. Acetyldihydrocodeine, Mirtazapine, Medifoxamine, Tianeptine, Pivagabine, Ven 50 Acetylmethadol, Acetylmethadol, Alfentanil, Allobarbital, lafaxine, Milnacipran, Reboxetine, Gepirone, Duloxetine, Allylprodin, Allylprodine, Alphacetylmethadol except levo Agomelatine, Desvenlafaxine, Centrally acting sympathomi alphacetylmethadol, Alpha-ethyltryptamine, Alphameprod metics, Amfetamine, Dexamfetamine, Lisdexamfetamine, ine, Alphamethadol, Alphamethadol, Alpha-Methylfentanyl, Metamfetamine, Methylphenidate, Dexmethylphenidate, Alpha-Methylthiofentanyl, Alphaprodine, Alprazolam, Pemoline, Fencamfamin, Modafinil, Fenozolone, Atomoxet 55 Amfepramon, Amfetaminil, Amineptin, Aminorex, Amobar ine, Fenetylline, Xanthine derivatives, Caffeine, Propento?yl bital, Amphetamine, Dextroamphetamine, Amylnitrit (all line. Other psychostimulants and nootropics, Meclofenoxate, isomers of the amyl group), Anabolic steroids, Anileridine, Pyritinol, Piracetam, Deanol, Fipexide, Citicoline, Oxirac Aprobarbital, Barbital, Barbituric acid derivative, BDB (3,4- etam, Pirisudanol, Linopirdine, Nizofenone, Aniracetam, methylenedioxyphenyl)-2-butanamine), Benzethidin, Ben Acetylcarnitine, Idebenone, Prolintane, Pipradrol, Pramirac 60 Zethidine, Benzoylecgonine, BenZphetamine, BenZphet etam, Adrafinil, Vinpocetine; amine, Benzylmethylketon, Benzylmorphine, Anti-dementia active Subtances. Such as, for example: Betacetylmethadol, Beta-Hydroxy-3-methylfentanyl, Beta Anticholinesterases, Tacrine, Donepezil, Rivastigmine, Gal Hydroxyfentanyl, Betameprodine, Betameprodine, antamine. Other anti-dementia drugs, Memantine, Ginkgo Betamethadol, Betaprodine, Bezitramide, Bezitramide, biloba; 65 Boldenone, Brolamfetamin, Bromazepam, Brotizolam, Other nervous system active Substances, such as, for Bufotenine, Buprenorphine. Butabarbital, Butalbital, Buto example: Parasympathomimetics, Anticholinesterases, Neo barbital, Butorphanol, BZP (A 2)(1-benzylpiperazin), US 9,023,394 B2 15 16 Camazepam, Cannabis, Carfentanil, Catha edulis, Cathine, peridine, Propiram, Psilocybine, Psilocyn, Pyrovalerone, Cathinone, Chloral betaine, Chloral hydrate, Chlordiazep Quazepam, Racemethorphane, Racemoramide, Racemor oxide, Chlorhexadol, Chlorotestosterone (same as clostebol), phane, Remifentanil, Salvia divinorum, Salvinorin A, Seco Chlorphentermine, Clobazam, Clonazepam, ClonitaZene, barbital, Secobarbital, Sibutramine, SPA, Stanolone, Stano Clonitazene, Clorazepate, Clortermine, Clostebol, Clotiaz Zolol, Sufentanil, Sulfondiethylmethane, epam, Cloxazolam, Coca Leaves, Cocaine, Codeine, Codeine Sulfonethylmethane, Sulfonmethane, Talbutal, Temazepam, & isoquinoline alkaloid, Codeine methylbromide, Codeine Tenamfetamin, Testolactone, Testosterone, Tetrahydrocan N-oxide, Codoxim, Cyclobarbital (Hexemal NFN), nabinols, Tetrazepam, TFMPP (1-(3-triflourmethylphenyl) Cyprenorphine, Dehydrochlormethyltestosterone, piperazine). Thebacon, Thebaine. Thiamylal. Thiofentanyl, Delorazepam, Desomorphine, Dexamfetamine, Dexfenflu 10 Thiopental, Tiletamine & Zolazepam in Combination, Tili ramine, Dexmethylphenidate, Dextromoramide, Dextropro dine, Trenbolone, Triazolam, Trimeperidine, Vinbarbital, poxyphene, Diacetylmorphine, Diampromide, Diazepam, Zaleplon, Zipeprol, Zolpidem and Zopiclon. Dichloralphenazone, Diethylpropion, Diethylthiambutene, Other suitable examples of active drug substances suitable Diethyltryptamine. Difenoxin, Dihydrocodeine, Dihydroet for use in the pharmaceutical compositions described herein orphine, Dihydromorphine, Dihydrotestosterone, 15 include, for example, alfentanil, allylprodine, alphaprodine, Dimenoxadol, Dimepheptanol, Dimethylthiambutene, Dim aniloridine, benzylmorphine, bezitramide, buprenorphine, ethyltryptamine, Dioxaphetylbutyrate, Diphenoxylate, Dipi butophanol, clonitaZene, codeine, cyclazocine, desomor panone, Diprenorphine, Dronabinol, Drostanolone, Drote phine, dextromoramide, dezocine, diapromide, dihydroco banol, Ecgonine, Estazolam, EthchlorVynol, Ethinamate, deine, dihydromorphine, dimenoxadol, dimephetanol, dim Ethyl loflazepate, Ethylestrenol, Ethylmethylthiambutene, ethylthiambutene, dioxaphetyl butyrate, dipipanone, Ethylmorphine, Ethylmorphine, Eticyclidin, Etilamfetamine, eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl Etonitazene, Etorphine, Etoxeridine, Etryptamine, Fencam morphine, etonitaZene, fentanyl, heroin, hydrocodone, famin, Fenethylline, Fenetyline, Fenfluramine, Fenpro hydromorphone, hydroxypethidine, isomethadone, dextro porex, Fentanyl. Fludiazepam, Flunitrazepam, Fluoxymes propoxyphene, ketobemidone, levallorphan, levorphanol, terone, Flurazepam, Formebolone, Fungi and Spores of the 25 levophenacylmorphan, lofentanil, meperidine, meptazinol, sepcies Psilocype Semilanceata, Furethidine, Gammahy metazocine, methadone, metopon, morphine, morphine droxybutanic acid, Glutethimide, Halazepam, Haloxazolam, 6-glucuronide, morphine 3-glucuronide, myrophine, nalbu Heroine, Hydrocodone, Hydrocodone & isoquinoline alka phine, narccine, nicomorphine, norlevorphanol, normetha loid, Hydromorphinol, Hydromorphone, Hydroxypethidine, done, nalorphine, normorphine, norpipanone, opium, oxyc Ibogaine, Isobutylnitrit, Isomethadone, Ketamine, Keta 30 odone, oxycodeine, oxymorphone, papaveretum, Zolam, Ketobemidone, Levamfetamine, Levo-alphacetyl pentazocine, phenadoxone, phenomorphan, phenazocine, methadol, Levo-methamphetamine, Levomethorphan, Levo phenoperidine, piminodine, piritramide, propheptazine, moramide, Levophenacylmorphan, Levorphanol, promedol, properidine, propiram, propoxyphene, Sufentanil, Lisdexamfetamin, Loprazolam, Lorazepam, Lorimetazepam, tilidine, tramadol, thebaine, levo-alphacetylmethadol Lysergic acid, Lysergic acid amide, Lysergic acid diethyla 35 (LAAM), remifentanil, carfentanyl, ohmefentanyl, MPPP mide, Marijuana, Mazindol, MBDN (N-methyl-1-(3.4-meth prodine, PEPAP levomethorphan, etorphine, lefetamine, lop ylenedioxyphenyl)-2-butanamine), mCPP (1-(3-chlorphe eramide, diphenoxylate or pethidine. nyl)piperazine), Mebutamate, Mecloqualone, Medazepam, Even further examples of active drug substances suitable Mefenorex, MeOPP (1-(4-methoxyphenyl)piperazine), for use in the pharmaceutical compositions described herein Meperidine, Meperidine intermediate, Meprobamate, Mes 40 include anabolic steroids, cannabis, cocaine and diazepam. caline, Mesocarb, Mesterolone, Metamfetamine, Metazo In one embodiment, the active substance is selected from cine, Methadone, Methadone intermediate, Methamphet the group consisting of the therapeutic classes including non amine, Methandienone, Methandranone, Methandriol, steroidal anti-inflammatory Substances and antirheumatic Methandrostenolone, Methaqualone, Methcathinone, Meth active Substances. enolone, Methohexital, Methyldesorphine, Methyldihydro 45 In other embodiments, the active substance is selected morphine, Methylphenidate, Methylphenobarbital (me from therapeutic classes including analgesics, opioids, anti phobarbital), Methyltestosterone, Methyprylone, Metopone, pyretics, anaesthetics, antimigraine agents, antiepileptics, Mibolerone, Midazolam, Modafinil, Moramide-intermedi anti-parkinson agents, dopaminergic agents, antipsychotics, ate, Morpheridine, Morphine, Morphine methylbromide, anxiolytics, sedatives, antidepressants, psychoStimulants Morphine methylsulfonate, Morphine-N-oxide, Myrophine, 50 agents, dopamine, noradrenaline, nicotinic, alfa-andrenergic, N,N-Dimethylamphetamine, Nabilone, Nalorphine, Nan serotonin, H antagonists used for ADHD and nootropics drolone. N-Ethyl-1-phenylcyclohexylamine. N-Ethyl-3-pip agents used in addictive disorders. eridyl benzilate. N-Ethylamphetamine, N-Hydroxy-3,4-me In still further embodiments, the active substance is thylenedioxyamphetamine, Nicocodeine, Nicocodine, selected from therapeutic classes including anaesthetics, cen Nicodicodine, Nicomorphine, Nimetazepam, Nitrazepam, 55 trally-acting analgesics, sedative-hypnotics, anxiolytics, N-Methyl-3-piperidyl benzilate, Noracymethadol, Norco appetite Suppressants, decongestants, antitussives, antihista deine, Nordiazepam, Norethandrolone, Norlevorphanol, mines, antiemetics, antidiarrheals, and drugs used to treat Normethadone, Normorphine, Norpipanone, Norpipanone, narcolepsy and attention deficit hyperactivity disorder. Opium, Oxandrolone, Oxazepam, Oxazolam, Oxycodone, In certain embodiments, the active drug Substance is asso Oxymesterone, Oxymetholone, Oxymorphone, Para-Fluoro 60 ciated with abuse syndromes and the active drug Substance fentanyl, Parahexyl, Paraldehyde, Pemoline, Pentazocine, may, for example, be selected from opioids, CNS depressants, Pentobarbital, Petrichloral, Peyote, Phenadoxone, Phenam CNS stimulants, cannabinoids, nicotine-like compounds, promide, Phenazocine, Phencyclidine, Phendimetrazine, glutamate antagonists and N-methyl-D-aspartate (NMDA) Phenmetrazine, Phenobarbital, Phenomorphan, Phenoperi antagonists. dine, Phentermine, Phenylacetone, Pholcodine, Piminodine, 65 In specific embodiments, the active drug Substance is an Pinazepam, Pipradrole, Piritramide, PMMA (param analgesic. Examples of analgesics Suitable for use in the ethyxymethyl amphetamine), Prazepam, Proheptazine, Pro pharmaceutical compositions and methods described herein US 9,023,394 B2 17 18 include, for example, Opioids, Natural opium alkaloids, Mor potassium salts, alkaline earth metal salts such as, e.g., cal phine, Opium, Hydromorphone, Nicomorphine, Oxycodone, cium and magnesium salts, and salts with organic or inorganic Dihydrocodeine, Diamorphine, Papaveretum, Codeine, Phe acids like e. g. hydrochloric acid, hydrobromic acid, nitric nylpiperidine derivatives, Ketobemidone, Pethidine, Fenta acid, Sulfuric acid, phosphoric acid, citric acid, formic acid, nyl, Diphenylpropylamine derivatives, Dextromoramide, Pir maleic acid, Succinic acid, tartaric acid, methansulphonic itramide, Dextropropoxyphene, Bezitramide, Methadone, acid, toluenesulphonic acid etc or tartrate acid. In particular Benzomorphan derivatives, Pentazocine, Phenazocine, Ori embodiments, pharmaceutically acceptable opioid salts may pavine derivatives, Buprenorphine, Morphinan derivatives, be selected from the group consisting of sulphate salts, hydro Butorphanol, Nalbuphine, Tilidine, Tramadol, Dezocine, chloride salts and bitartrate salts. Salicylic acid and derivatives, Acetylsalicylic acid, Aloxiprin, 10 The term “solvates' includes hydrates or solvates wherein Choline salicylate, Sodium salicylate, Salicylamide, Sal other Solvates than water are involved such as, for example, salate, Ethenzamide, Morpholine salicylate, Dipyrocetyl, organic solvents like chloroform and the like. Benorilate. Diflunisal, Potassium salicylate, Guacetisal, Car Furthermore, the active drug Substance may be in any of its basalate calcium, Imidazole Salicylate, Pyrazolones, crystalline, polymorphous, semi-crystalline, amorphous or PhenaZone, Metamizole sodium, AminophenaZone, Propy 15 polyamorphous forms and mixtures thereof. phenaZone, NifenaZone, Anilides, Paracetamol, Phenacetin, The concentration of the active drug Substance in a com Bucetin, Propacetamol. Other analgesics and antipyretics, position for use according to the invention depends on the Rimazolium, Glafenine, Floctafenine, Viminol, Nefopam, specific active drug Substance, the disease to be treated, the Flupirtine, Ziconotide. condition of the patient, the age and gender of the patient etc. In certain Such embodiments, the active drug Substance is The above-mentioned active drug Substances are well-known an opioid. Where an opioid is included as an active drug active drug Substances and a person skilled in the art will be Substance, the opioid may be selected from naturally occur able to find information as to the dosage of each active drug ring opioids, synthetic opioids and semisynthetic opioids. Substance and, accordingly, he will know how to determine In another embodiment, the active drug Substance is the amount of each active drug Substance in a composition. selected from Amfetamine, Dexamfetamine, Lisdexamfe 25 The active drug Substance is typically present in a matrix tamine, Metamfetamine, Methylphenidate, Dexmethylpheni composition of the invention in a concentration amount of date and combinations thereof. from 0.01-99% w/w such as, for example, from about 0.01 to In some embodiments of pharmaceutical compositions about 90% w/w, from about 0.01 to about 80% w/w, from including an opioid, the opioid is selected from buprenor about 0.01 to about 70% w/w, from about 0.01 to about 50% phine, codeine, dextromoramide, dihydrocodeine, fentanyl. 30 w/w, from about 0.01 to about 45% w/w or from about 0.01 to hydrocodone, hydromorphone, morphine, pentazocine, oxy about 40% w/w. codeine, oxycodone, oxymorphone, norhydrocodone, When the active drug substance is an opioid, such as mor noroxycodone, morphine-6-glucuronode, tramadol and dihy phine, oxycodone, hydromorphone or hydrocodone or salts dromorphine. thereof, then said opioid is typically present in the matrix Where an opioid is used as an active drug Substance, the 35 compositions in a concentration of in the range of 1 to 70% opioid, such as morphine, hydrocodone, hydromorphone or w/w, for example in the range of 1 to 60% w/w, such as in the oxycodone, may be present in any of its crystalline, polymor range of 1 to 50% w/w, such as in the range of 1 to 45% w/w, phous, or amorphous forms. Furthermore, an opioid used as for example in the range of 1 to 40% w/w, such as in the range an active drug Substance may be present in one or more forms of 1 to 30% w/w, for example in the range of 1 to 20% w/w, selected its crystalline, polymorphous, or amorphous forms. 40 such as in the range of 1 to 17% w/w. In specific embodiments of the pharmaceutical composi When the active drug Substance is an opioid, such as mor tions including an opioid as an active drug Substance, the phine or salts thereof, then said opioid is typically present in active drug Substance is selected from morphine, oxycodone, the matrix compositions in a concentration of in the range of hydrocodone, hydromorphone, norhydrocodone, oxymor 1 to 70% w/w, for example in the range of 1 to 60% w/w, such phone, noroxycodone, morphine-6-glucuronode and phar 45 as in the range of 1 to 55% w/w, for example in the range of 1 maceutically acceptable salts of any of the aforementioned, to 50% w/w, such as in the range of 1 to 40% w/w, for example Such as from the group consisting of oxycodone hydrochlo in the range of 1 to 35% w/w, such as in the range of 1 to 30% ride, hydrocodone bitartrate, hydromorphone hydrochloride w/w, for example in the range of 1 to 20% w/w, such as in the and morphine Sulphate pentahydrate. range of 1 to 17% W/w, or the opioid, Such as morphine, may All of the above mentioned active drug Substances may 50 be present in the matrix in the range of 5 to 60% w/w, for also be in the form of pharmaceutically acceptable salts, example in the range of 20 to 60% w/w, such as in the range uncharged or charged molecules, molecular complexes, Sol of 30 to 60% w/w, for example in the range of 30 to 55% w/w, Vates or anhydrates thereof, and, if relevant, isomers, enanti such as in the range of 35 to 55% w/w. omers, racemic mixtures, and mixtures thereof. In one embodiment, the matrix composition comprises an In particular, the pharmaceutical compositions described 55 opioid active drug Substance in an amount ranging from 1 to herein may comprise pharmaceutically acceptable salts of 17% w/w, such as 10 to 17% w/w, for example 15 to 17% w/w, any of the above mentioned active drug Substances. such as 16% w/w. In one such embodiment, the opioid is The term “pharmaceutically acceptable salts' of an active selected from morphine and pharmaceutically acceptable drug Substance includes alkali metal salts such as, for salts thereof. In other embodiments including an opioid as an example, Sodium or potassium salts, alkaline earth metal salts 60 active agent, the matrix composition includes the opioid Such as, for example, calcium and magnesium salts, and salts active drug Substance in an amount greater than 17% W/w, with organic or inorganic acid like, for example, hydrochloric such as in the range of 20 to 60% w/w, and in one such acid, hydrobromic acid, nitric acid, Sulfuric acid, phosphoric embodiment, the opioid drug Substance is selected from mor acid, citric acid, formic acid, maleic acid, Succinic acid, tar phine and pharmaceutically acceptable salts thereof. taric acid, methansulphonic acid, toluenesulphonic acid etc. 65 In another embodiment, the matrix composition comprises The term “pharmaceutically acceptable salts' of an opioid an opioid active drug Substance in an amount ranging from 1 includes alkali metal salts such as, for example, Sodium or to 70% w/w, for example in the range of 1 to 60% w/w, such US 9,023,394 B2 19 20 as in the range of 1 to 50% w/w, for example in the range of 1 15 mm, 7.5 to 10 mm, 7.5 to 8 mm long, even when the to 45% w/w, such as in the range of 1 to 40% w/w, such as in pharmaceutical composition is prepared for continued the range of 1 to 30% w/w, for example in the range of 5 to administration of an active drug Substance over an interval of 20% w/w, such as in the range of 10 to 20% w/w, for example about 22 to about 28 hours, such as 24 hours between indi in the range of 12 to 15% w/w. In certain such embodiments, vidual administrations. In certain Such embodiments, phar the opioid active agent is hydrocodone bitaritrate. maceutical composition is prepared to exhibit a length of 7.5 In another embodiment, the matrix composition comprises . a high load of an opioid active drug Substance, wherein a high Neither Hydrocodone nor Oxycodone are metabolized by load is at least 15% w/w, preferably in the range of 15 to 70% glucuronidation in the liver, but are primarily demethylated w/w, for example in the range of 15 to 60% w/w, such as in the 10 via CYP pathways. Nevertheless, pharmaceutical composi range of 15 to 50% w/w, for example in the range of 15 to 45% tions as disclosed herein that include hydrocodone or oxyc w/w, such as in the range of 15 to 40% w/w, such as in the odone as an active drug Substance are useful for providing range of 15 to 30% w/w, for example in the range of 20 to 30% continued administration of the active drug Substance over an w/w, such as in the range of 24 to 28% w/w. In certain such interval of about 20 to 28 hours (such a 24 hour interval) embodiments, the opioid active agent is hydrocodone bitar 15 between individual administrations. trate. Pharmaceutical compositions comprising active drug Sub In yet another embodiment, the matrix composition com stances which are essentially not subject to entero-hepatic prises oxycodone hydrochloride as an opioid active drug Sub recirculation, in general, may be longer than other pharma stance. In certain Such embodiments, the matrix composition ceutical compositions. Thus, pharmaceutical compositions includes oxycodone hydrochloride in an amount ranging comprising active drug Substances which are not subject to from 1 to 70% w/w, for example in the range of 1 to 60% w/w, entero-hepatic recirculation (e.g., oxycodone or hydrocodone such as in the range of 1 to 50% w/w, for example in the range or pharmaceutically acceptable salts thereof) may have a of 1 to 45% w/w, such as in the range of 1 to 40% w/w, such length in a range selected from 8 to 15 mm, 8 to 12 mm, and as in the range of 1 to 30% w/w, for example at least 15% w/w, 8 to 10 mm, when the pharmaceutical composition is pre preferably in the range of 15 to 70% w/w, for example in the 25 pared for continued administration of the active drug Sub range of 15 to 60% w/w, such as in the range of 15 to 50% stance over an interval of about 22 to 28 hours, such as a 24 w/w, such as in the range of 15 to 45% w/w, for example in the hour interval, between individual administrations. range of 15 to 40% w/w, such as in the range of 15 to 30% A pharmaceutical composition as described herein may w/w, for example in the range of 20 to 30% w/w, such as in the comprise one active drug Substance or more than one different range of 24 to 28% w/w. 30 active drug Substances. Typically, the amount of the active In certain embodiments, the matrix compositions comprise Substance corresponds to a daily or part of a daily therapeutic a low load of the active drug substance, such as an opioid. A dose. low load is generally less than 50% w/w of the active drug Pharmaceutical compositions as described herein are Suit Substance. For example, in certain Such embodiments, the able for use for both water soluble as well as slightly soluble matrix compositions may include an active drug Substance in 35 or insoluble active Substances. an amount selected from less than 45% w/w and less than Pharmaceutically Acceptable Excipients 40% w/w. The matrix composition of the formulations described A pharmaceutical composition according to the invention herein may also contain other excipients in order to achieve containing an active drug Substance as described herein above the one or more desired properties, such as a stability of the is typically formulated for oral administration. In one 40 active drug Substance or the pharmaceutical composition embodiment, the matrix composition provides for adminis itself, loading of the active drug Substance or delivery char tration only once daily. In particular such embodiments, for acteristics, such as release rate or release profile of an active the pharmaceutical composition a length of in the range of 7.5 drug Substance. Further, a matrix composition may include to 15 mm, preferably 8 to 15 mm, more preferably 8 to 10 mm. excipients that facilitate manufacture and production of dos The matrix composition may also provide for administration 45 age forms suitable for administration to individuals in need twice daily, which in particular is the case for the pharmaceu thereof. tical composition exhibits a length shorter than 8 mm, Such as A Suitable pharmaceutically acceptable excipient for use in a length in a range selected from 4 to 8 mm, 5.5 to 8 mm, or a matrix composition of the invention may be selected from 5.8 to 8 mm. fillers, diluents, disintegrants, glidants, pH-adjusting agents, Certain active drug Substances may be subject to entero 50 Viscosity adjusting agents, solubility increasing or decreasing hepatic recirculation. Thus, for example, morphine, hydro agents, osmotically active agents and solvents. morphone and other opioids are metabolised mainly in the Suitable excipients include conventional tablet or capsule liver to both active and inactive compounds that are excreted excipients. These excipients may be, for example, diluents in urine and bile. Morphine and hydromorphone are excreted Such as dicalcium phosphate, calcium Sulfate, lactose or partly in the bile as water-soluble glucuronides. In the gut, 55 Sucrose or other disaccharides, cellulose, cellulose deriva these glucuronides are metabolised by the normal gut flora to tives, kaolin, mannitol, dry starch, glucose or other monosac the parent opioid compound and reabsorbed (entero-hepatic charides, dextrin or other polysaccharides, Sorbitol, inositol recirculation), which may prolong the residence of morphine or mixtures thereof binders such as alginic acid, calcium and hydromorphone and theirs metabolites in the systemic alginate, Sodium alginate, starch, gelatin, Saccharides (in circulation. 60 cluding glucose, Sucrose, dextrose and lactose), molasses, Pharmaceutical compositions comprising active drug Sub panwar gum, ghatti gum, mucilage ofisapolhusk, carboxym stances subject to entero-hepatic recirculation may in general ethylcellulose, methylcellulose, Veegum, larch arabolactan, be shorter than other pharmaceutical compositions. Thus, polyethylene glycols, ethylcellulose, water, alcohols, waxes, pharmaceutical compositions comprising active drug Sub polyvinylpyrrolidone such as PVP K90 or mixtures thereof; stances Subject to entero-hepatic recirculation (e.g., mor 65 lubricants such as talc, silicium dioxide, magnesium Stearate, phine, hydromorphone or pharmaceutically acceptable salts calcium Stearate, Stearic acid, hydrogenated vegetable oils, thereof) may have a length of in a range selected from 7.5 to sodium benzoate, sodium chloride, leucine, carbowax 4000, US 9,023,394 B2 21 22 magnesium lauryl Sulfate, Sodium laurilsulfate, Stearyl alco oxyethylene 50 Stearate, macrogol ethers, cetomacrogol hol, Polysorbate 20, Polysorbate 60, Polysorbate 80, Mac 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, rogol Stearate, Macrogol lauryl ether, Stearoyl macrogolglyc poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate erides, Sorbitan stearate, Sorbitan laurate, Macrogol glycerol 40, polysorbate 60, polysorbate 65, polysorbate 80, polysor hydroxy Stearat, colloidal silicon dioxide and mixtures bate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan thereof, disintegrants such as starches, clays, cellulose deriva monopalmitate, Sorbitan monostearate, Sorbitan sesqui tives including crosscarmellose, gums, aligns, various com oleate, Sorbitan trioleate, Sorbitan tristearate and Sucrose binations of hydrogencarbonates with weak acids (e.g., esters, amyl oleate, butyl oleate, butyl stearate, diethylene Sodium hydrogencarbonate?tartaric acid or citric acid) glycol monolaurate, glycerol tributyrate, Cumar W-1, Cumar crosprovidone, sodium starch glycolate, agar, cation 10 MH-1, Cumar V-1, Flexol B-400, monomeric polyethylene exchange resins, citrus pulp, Veegum, glycolate, natural ester, Piccolastic A-5, Piccalastic A-25, Beckolin, Clorafin sponge, bentonite. Sucralfate, calcium hydroxyl-apatite or 40, acetyl tributyl citrate, acetyl triethyl citrate, benzyl ben mixtures thereof. Zoate, butoxyethyl Stearate, butyl and glycol esters of fatty A matrix composition as described herein may comprise acids, butyl diglycol carbonate, butyl ricinoleate, butyl one or more gelling agents. Examples are polymers selected 15 phthalyl butyl glycolate, camphor, dibutyl sebacate, dibutyl from the group consisting of modified or unmodified water tartrate, diphenyl oxide, glycerine, HB-40, hydrogenated soluble natural polymers such as glucomannan, galactan, glu methyl ester of rosin, methoxyethyl oleate, monoamylphtha can, polygalacturonic acid, polyxylane, polygalactoman late, Nevillac 10, Paracril 26, technical hydroabietyl alcohol, nans, polyxyloglycan, arabinogalactan, starch, cellulose, chi Methylene glycol dipelargonate, Solid aliphatic alcohols and tosan, alginate, fibrin, collagen, gelatin, amylopectin, pectin mixtures thereof. including low methylated or methoxylated pectins, dextran; Exemplary stabilizers (chemical) include TPG, for synthetic polymers such as PVA and PVB; and hydrogels example, in the form of TPGS (Vitamin E Polyehtylene gly made from the polymers or combined polymers mentioned col succinate) and BHT, BHA, t-butyl hydroquinone, butyl above and or from polymers originated from: HEMA, hydroxy toluene, calcium ascorbate, gallic acid, hydro HEEMA, MEMA, MEEMA, EDGMA, NVPVAc, AA, acry 25 quinone, maltol, octyl gallate, Sodium bisulfite, sodium lamide, MAA, HPMA, PEGA, PEGMA, PEGDMA, metabisulfite, tocopherol and derivates thereof, citric acid, PEGDA, and/or PEGDMA, hydroxypropyl methylcellulose, tartaric acid, and ascorbic acid. Thus, in one embodiment, a hydroxypropyl cellulose, methylcellulose, hydroxyethyl matrix composition as described herein comprises TPGS and/ ncellulose, ethylcellulose, hydroxypropyl methylcellulose or BHT. Other stabilisers include trivalent phosphorous, such phthalate, hydroxypropyl methylcellulose Acetate Succinate 30 as, for example, phosphite, phenolic antioxidants, hydroxy or other cellulose derivates, carboxymethylcellulose sodium, lamines, lactones such as Substituted benzofuranones, hin carboxymethylcellulose calcium, carrageenans, guar gum, dered phenols, thiosynergists and/or hindered amines, acids gellan gum, Xanthan gum, tragacanth and Arabic gum. (ascorbic acid, erythorbic acid, etidronic acid, hypophospho Furthermore, the pharmaceutical compositions described rous acid, nordihydroguaiaretic acid, propionic acid etc.), herein may comprise one or more agents selected from Sweet 35 phenols, dodecyl gallate, octyl gallate, 1,3,5-trihydroxyben ening agents, flavouring agents and colouring agents, in order Zene, organic and inorganic salts (calcium ascorbate, sodium to provide an elegant and palatable preparation. Examples ascorbate, sodium bisulphite, sodium metabisulfite, sodium include maltol, citric acid, water soluble FD&C dyes and Sulfite, potassium bisulphite, potassium metabisulphite), mixtures thereof with corresponding lakes and direct com esters (calcium ascorbate, dilauryl thiodipropionate, dimyri pression Sugars such as Di-Pac from Amstar. In addition, 40 styl thiodipropionate, distearyl thiodipropionate), pyranon coloured dye migration inhibitors such as tragacanth, acacia (maltol), and vitamin E (tocopherol, D-alpha-tocopherol, or attapulgite talc may be added. Specific examples include DL-alpha-tocopherol, tocopheryl acetate, d-alpha-toco Calcium carbonate, 1,3,5-trihydroxybenzene, Chromium-co pheryl acetate, d1-alpha-tocopheryl acetate. However, other balt-aluminium oxide, ferric ferrocyanide, Ferric oxide, Iron anti-oxidative agents known in the art may also be used. Other ammonium citrate, Iron (III) oxide hydrated, Iron oxides, 45 suitable stabilizers may be selected from, for example, sorbi Carmine red, Magnesium carbonate and Titanium dioxide. tol glyceryl tricitrate. Sucrose octaacetate. Plasticizers may be incorporated in the pharmaceutical In one embodiment, a matrix composition as described compositions according to the present description. A Suitable herein comprises one or more stabilizers selected from above plasticizer may be selected from mono- and di-acetylated mentioned group of stabilizers. In one such embodiment, the monoglycerides, diacetylated monoglycerides, acetylated 50 matrix composition comprises butylhydoxytoluene as a sta hydrogenated cottonseed glyceride, glyceryl cocoate, Poly bilizer. In another Such embodiment, the matrix composition ethylene glycols or polyethylene oxides (e.g., with a molecu comprises TPGS as a stabilizer. lar weight of about 1,000-500,000 daltons), dipropylene gly A release modifier may be incorporated in a matrix com col salicylate glycerin, fatty acids and esters, phthalate esters, position as described herein. A suitable release modifier may phosphate esters, amides, diocyl phthalate, phthalyl glyco 55 be selected from fatty acids and esters, fatty alcohols, cetyl late, mineral oils, hydrogenated vegetable oils, vegetable oils, alcohol, Stearyl alcohol, mineral oils, hydrogenated vegetable acetylated hydrogenated soybean oil glycerides, Castor oil, oils, vegetable oils, acetylated hydrogenated Soybean oil acetyl tributyl citrate, acetyl triethyl citrate, methyl abietate, glycerides, Castor oil, phosphate esters, amides, phthalate nitrobenzene, carbon disulfide, beta-naphtyl salicylate, Sor esters, glyceryl cocoate oleyl alcohol, myristyl alcohol, bitol, sorbitol glyceryl tricitrate, fatty alcohols, cetostearyl 60 Sucrose octaacetate, diacetylated monoglycerides, diethylene alcohol, cetyl alcohol, Stearyl alcohol, oleyl alcohol, myristyl glycol monostearate, ethylene glycol monostearate, glyceryl alcohol. Sucrose octaacetate, alfa->-tocopheryl polyethyl monooleate, glyceryl monostearate, propylene glycol ene glycol succinate (TPGS), tocopheryl derivative, diacety monostearate, macrogol esters, macrogol Stearate 400, mac lated monoglycerides, diethylene glycol monostearate, eth rogol stearate 2000, polyoxyethylene 50 stearate, macrogol ylene glycol monostearate, glyceryl monooleate, glyceryl 65 ethers, cetomacrogol 1000, lauromacrogols, poloxamers, monostearate, propylene glycol monostearate, macrogol polyvinyl alcohols, Sorbitan monolaurate, Sorbitan esters, macrogol Stearate 400, macrogol Stearate 2000, poly monooleate, Sorbitan monopalmitate, Sorbitan monostearate, US 9,023,394 B2 23 24 Sorbitan sesquioleate, Sorbitan trioleate, Sorbitan tristearate, sium Succinate, calcium Succinate, sodium citrate, potassium ethylcellulose, cellulose acetate, cellulose propionate, cellu citrate, calcium citrate, Sodium tartrate, potassium tartrate or lose nitrate, cellulose derivative selected from the group con calcium tartrate. sisting of methylcellulose, carboxymethylcellulose and salts Suitable inorganic salts for that may be used in a matrix thereof, cellulose acetate phthalate, microcrystalline cellu composition as described herein include, for example, lose, ethylhydroxyethylcellulose, ethylmethylcellulose, Sodium chloride, potassium chloride, calcium chloride or hydroxyethylcellulose, hydroxyethylmethylcellulose, magnesium chloride. hydroxypropylcellulose, hydroxypropylmethylcellulose, The matrix composition may comprise at least one saccha hydroxymethylcellulose and hydroxymethylpropylcellulose, ride. Where a saccharide is included in a matrix composition 10 as described herein, the saccharide may be selected from, for cellulose acetate, polylactic acid or polyglycolic acid and example, glucose, ribose, arabinose, Xylose, lyxose, Xylol. copolymers thereof, methacrylates, a co-polymer of meth allose, altrose, inosito, glucose, Sorbitol, mannose, gulose, acrylate-galactomannan etc., Polyvinyl alcohols, glycerin Glycerol, idose, galactose, talose, mannitol, erythritol, ribi ated gelatine and cocoa butter. tol. Xylitol, maltitol, isomalt, lactitol. Sucrose, fructose, lac Other suitable release modifiers may be selected frominor 15 tose, dextrin, dextran, amylase or Xylan. In one such embodi ganic acids, inorganic bases, inorganic salts, organic acids or ment, the matrix composition comprises mannitol. bases and pharmaceutically acceptable salts thereof, saccha The matrix composition may also comprise polyethylene rides, oligosaccharides, polysaccharides, polyethylene gly glycol derivatives such as, for example, polyethylene glycol col derivatives and cellulose and cellulose derivatives. di(2-ethylhexoate), polyethylene glycols (200-600 daltons) Alternatively or additionally, a matrix composition accord or polyethylene oxides, for example, with an average molecu ing to the present description may include a pharmaceutically lar weight of about 800-500,000 daltons, typically about acceptable excipient selected from a mono-, di-, oligo, poly 1,000-100,000 daltons, more typically 1,000-50,000 daltons, carboxylic acid or amino acids such as, for example, acetic especially about 1,000-10,000 daltons, in particular about acid, Succinic acid, citric acid, tartaric acid, acrylic acid, 1,500-5,000 daltons, or mixtures thereof. benzoic acid, malic acid, maleic acid, Sorbic acid etc., aspartic 25 The matrix composition may also comprise cellulose and/ acid or glutamic acid etc. or cellulose derivatives selected from the group consisting of Suitable organic acids that may be included in the compo methylcellulose, carboxymethylcellulose and salts thereof, sitions described herein include, for example, acetic acid/ microcrystalline cellulose, ethylhydroxyethylcellulose, eth ethanoic acid, adipic acid, angelic acid, ascorbic acid/vitamin ylcellulose, cellulose acetate, cellulose proprionate, cellulose 30 nitrate, cellulose acetate phthalate, ethylmethylcellulose, C, carbamic acid, cinnamic acid, citramalic acid, formic acid, hydroxyethylcellulose, hydroxyethylmethylcellulose, fumaric acid, gallic acid, gentisic acid, glutaconic acid, glu hydroxypropylcellulose, hydroxypropylmethylcellulose, taric acid, glyceric acid, glycolic acid, glyoxylic acid, lactic hydroxymethylcellulose and hydroxymethylpropylcellulose. acid, levulinic acid, malonic acid, mandelic acid, oxalic acid, Preparation oxamic acid, pimelic acid, or pyruvic acid. 35 The pharmaceutical composition as well as the matrix Suitable inorganic acids that may be included in the com composition of the invention may be produced by various positions described herein include, for example, pyrophos methods which are either known perse in the pharmaceutical phoric, glycerophosphoric, phosphoric Such as ortho and industry or which, for example, are used in the production of meta phosphoric, boric acid, hydrochloric acid, or Sulfuric polymer-based materials, depending upon the desired acid. 40 embodiment and the materials employed in the composition Examples of Suitable inorganic compounds that may be in question. The compositions according to the present included in the compositions described herein include, for description may be produced by methods that are relatively example, aluminium. simple and inexpensive. Examples of organic bases that may be included in the Suitable preparation methods for compositions according compositions described herein include, for example, p-nitro 45 to the invention include extrusion, injection moulding, moul phenol. Succinimide, benzenesulfonamide, 2-hydroxy-2cy ding, tabletting, capsule filling, melt-processing, spray coat clohexenone, imidazole, pyrrole, diethanolamine, ethylene ing, micro encapsulation and other methods of preparing amine.tris(hydroxymethyl)aminomethane, hydroxylamine controlled release compositions. Also a combination of one or and derivates of amines, sodium citrate, aniline or hydrazine. more of the aforementioned may be employed. Examples of inorganic bases that may be included in the 50 The controlled release composition may be prepared by compositions described herein include, for example, alu several different methods. Many systems for controlled minium oxide Such as, for example, aluminium oxide trihy release are marketed and it is currently an aim for the industry drate, alumina, Sodium hydroxide, potassium hydroxide, cal to reduce the risk of dose dumping, drug abuse or alcohol cium carbonate, ammonium carbonate, ammonium induced dose dumping in each of the systems. hydroxide or KOH. 55 In other words, in addition to a less frequent administra Pharmaceutically acceptable salts of an organic acid that tion, one challenge in controlled release delivery may be may be included in the compositions described herein expressed by the goal of decreasing the incidence of adverse include, for example, an alkali metal salt or an alkaline earth effects and at the same time increasing the efficacy of the metal salt Such as, for example, sodium phosphate, sodium treatment. This may be obtained by an interaction between dihydrogenphosphate, disodium hydrogenphosphate etc., 60 the specific pharmacological properties of the active drug potassium phosphate, potassium dihydrogenphosphate, Substance and the matrix composition. potassium hydrogenphosphate etc., calcium phosphate, High concentrations or a fast rise in the concentration of dicalcium phosphate etc., sodium sulfate, potassium Sulfate, for example, opioids is a significant factor associated with calcium Sulfate, sodium carbonate, Sodium hydrogencarbon undesirable side effects, including the risk addiction. The fear ate, potassium carbonate, potassium hydrogencarbonate, cal 65 of addiction is often an obstacle for initiation of the otherwise cium carbonate, magnesium carbonate etc., sodium acetate, effective pain treatment with, for example, morphine, hydro potassium acetate, calcium acetate, sodium Succinate, potas codone or oxycodone. US 9,023,394 B2 25 26 Compositions for controlled release according as present context, cross sections are perpendicular to the axis of described herein may be prepared in numerous ways giving the cylinder. By way of example, if the cylindrical shape is rise to different release mechanisms. For example, the com elongated then the cross sections are perpendicular to the positions described herein may be prepared by 1, 2 or mul longitudinal axis. The cylindrical shape is typically elon tiple component injection mouldings, by conventional tablet gated. The cross section of a cylinder within the meaning of compression, by micro encapsulation, by 1, 2 or multiple the present description may have any two dimensional shape, component extrusions, by moulding, by capsule filling or by for example the cross section may be circular, oval, parabola, melt-processing. In cases where a preparation is needed in hyperbola, rectangular, triangular, otherwise angular, order to make the controlled release properties before/after polygonal, star shaped or an irregular shape. In preferred the above mentions preparation steps, the preparation may 10 embodiments of the invention the cross section is oval or also comprise separate steps as for example wet granulation, circular. In particular embodiments, the pharmaceutical com dry granulation, melt granulation, pelletizing, spray coating, positions described herein have a cylindrical shape, wherein electrostatic coating or other forms of controlled release one or both end(s) may be tapered, for example one or both forming preparation methods. end(s) may be rounded. Thus, the matrix may taper along the In a particular example, the composition is prepared by two 15 longitudinal axis, i.e. the area of the cross section may component injection moulding of a matrix composition and a decrease along the longitudinal axis towards one or both ends coating (which may be any of the coatings described herein of the matrix. below in the section “Coating) surrounding the matrix and Accordingly, the cylindrical shape of a pharmaceutical exposing at least one surface of the matrix, preferably the two composition according to the present description may for ends of the matrix composition for erosion governed release. example be an elliptic cylinder, a parabolic cylinder, a hyper A composition may also be produced by, for example, bolic cylinder or a prism. A prism within the present context moulding, injection moulding, multiple component injection is a cylinder whose cross-section is a polygon. moulding, co-extrusion of the coating with the matrix com FIG. 11 shows examples of specific pharmaceutical com position and the active drug Substance, extrusion and dip positions. The skilled person will appreciate that the depicted coating, injection moulding and dip coating, or by extrusion 25 shapes also may be applied to other pharmaceutical compo or injection moulding and solvent coating by spraying or sitions. Accordingly, the pharmaceutical compositions con dipping, or a combination of these methods. sisting of a matrix Surrounded by a coating according to the Geometry present invention may for example have any of the cylindrical As disclosed herein, the release mechanisms of the phar shapes shown in FIG. 11, wherein, FIG. 11 I-1 shows the 3 maceutical compositions described hereindepend, at least in 30 dimensional structure of around pharmaceutical composition part, on the geometry of the composition. For example, ero and FIG. 11 I-2 shows a 3 dimensional shape of a matrix, FIG. sion based release from a matrix depends on the area of the 11 II, III and IV show pharmaceutical compositions with an matrix exposed to the environment. In embodiments of the oval shape, wherein the cross section of the matrix has either pharmaceutical compositions described herein, wherein the an oval shape or a round shape (FIG. 11 II-4). The skilled opening(s) in the coating are of the same shape and size as the 35 person will appreciate that other shapes are also useful for the cross section of the matrix composition, erosion of the matrix pharmaceutical compositions described herein. For example, composition will depend upon the cross sectional area of the the matrix shown in FIG. 11 II-2 may also be a cylinder opening(s), with the rate of erosion (and therefore the rate of without a tapered end or it may have two tapered ends rather delivery of active drug Substance) increasing as the cross than one. sectional area of the matrix composition exposed by the one 40 FIG. 11 I-3 shows an exemplary pharmaceutical composi or more openings in the coating increases. The area of the tion. The pharmaceutical composition has a matrix with a matrix composition exposed to its surroundings (and there cylindrical part the length of which is designated F and the fore the delivery characteristics provided) may be manipu diameter designated C. The matrix further has a tapered end, lated by employment of a coat that is not subject to erosion the length of which is designated E and the diameter of the and thus covering areas of the matrix that should not be 45 part of the end which is shortest is designated A. The entire releasing sites. length of the matrix is designated B. The matrix is surrounded The geometric form of the composition may also be by a coating, which has a thickness of G in one end. The manipulated to achieve controlled release as described overall diameter of the pharmaceutical composition is desig herein. In one embodiment, the pharmaceutical composition nated D. FIG. 11 I-3 shows an example of a pharmaceutical has a geometric shape, which enables a Substantially constant 50 composition according to the present description, and it will Surface area of the matrix composition to become exposed be apparent to the skilled person that modifications may be during erosion of the matrix and delivery of an active drug made, for example pharmaceutical compositions as described Substance contained therein. herein may be produced without tapered ends, with two The pharmaceutical compositions described herein are tapered, with a coating that is uniformly thick, and/or wherein cylindrical compositions with optionally tapered end(s). It 55 the cross section of the matrix has either an oval shape or a follows, then, that the matrix composition included in Such round shape pharmaceutical compositions also exhibits a cylindrical The pharmaceutical composition as well as the matrix shape (optionally with tapered end(s)). The matrix composi composition used informing the pharmaceutical composition tion is Substantially Surrounded by a coating having at least may be a cylindrical shape with one tapered end or two one or two openings allowing exposure of at least one Surface 60 tapered ends. of said matrix to its Surroundings. Thus, the shape of the matrix may be defined by a main A cylindrical shape as contemplated herein may be any cylindrical body (herein referred to as “cylinder part of the geometrical shape having the same cross section area matrix”) optionally with one or two tapered ends. FIG.11 I-3, throughout the length of the geometrical shape. Thus, the for example, shows a cylinder part of the matrix defined by term "cylindrical shape” as used herein preferably refers to 65 FxC. The cylinder part of the matrix is in general completely any geometrical shape having the same cross section area cylindrical. In certain embodiments, the length of said cylin along an axis, preferably the longitudinal axis. Within the der part of the matrix (e.g., F in FIG. 11 I-3) is in the range of US 9,023,394 B2 27 28 7.5 mm to 15 mm, and may be selected from, for example, a those compositions having less than 50%. Such as less than range of 8 to 15 mm, a range of 8 to 10 mm, a range of 8.2 to 40% active drug Substance. Aforementioned cross-section 9.8 mm, a range of 8.4 to 9.6 mm, a range of 8.5 to 9.5 mm, a areas may be sued in preparation of pharmaceutical compo range of 8.7 to 9.3 mm, and a range of 8.9 to 9.1 mm. In sitions formulated for continued administration of an active specific Such embodiments, the length of said cylinderpart of 5 drug Substance over a period of time ranging from about 20 to the matrix may be selected from 9 mm, and 9.5 mm long 28 hours, such as those providing continued administration of along the longitudinal axis. Aforementioned lengths are in an active drug Substance over a period of time in a range particular relevant for pharmaceutical compositions formu selected from about 22 to 26 hours and about 23 to 25 hours. lated for continued administration of an active drug Substance In once Such embodiment, pharmaceutical compositions for over an interval ranging from about 20 to 28 hours. In certain 10 mulated for continued administration of an active drug Sub Such embodiments, the pharmaceutical composition is for stance over a period of 24 hours. mulated and produced for continued administration of an Thus, in specific embodiments, the cylinder part of the active drug substance over an interval selected from about 20 matrix has a length in a range selected from 7.5 to 15 mm and to 28 hours, about 22 to 26 hours, and about 23 to 25 hours. In 8 to 10 mm and a cross sectional area of at least 20 mm. For a specific Such embodiment, the pharmaceutical composition 15 example, the cylinder part of the matrix may have a length is formulated and produced for continued administration of selected from between 7.5 and 15 mm, and between 8 to 10 an active drug Substance over a 24 hour interval. mm and a cross sectional area of in the range of 20 to 100 In specific embodiments, the matrix is relatively long, Such mm, such as a length of the range of 8.5 to 9.5 mm and a cross as longer than 9 mm, for example in the range of 9 to 15 mm, sectional area in the range of 20 to 100 mm, for example a Such as in the range of 9 to 12 mm, for example approximately length of the range of 8.9 to 9.1 mm and a cross section area 9 mm, Such as approximately 10 mm, for example approxi of in the range of 20 to 100mm, such as a length of 9 mm and mately 11 mm, Such as approximately 12 mm, for example 9 a cross section area of in the range of 20 to 100 mm. In mm, Such as 10mm, for example 11 mm, Such as 12 mm long. another embodiment, the cylinderpart of the matrix may have Compositions of these longer lengths are Suitable for phar a length selected from between 7.5 and 15 mm and between 8 maceutical compositions formulated for continued adminis 25 to 10 mm and a cross section area of at least 1 mm. For tration of an active drug Substance over an interval selected example, in Such an embodiment, the cylinder part of the from a range of about 20 to 28 hours, about 22 to 26, and about matrix may have a length selected from between 7.5 to 15 mm 23 to 25 hours. In certain such embodiments, the pharmaceu and between 8 to 10 mm and a cross section area in a range tical composition is formulated and produced for continued selected from 1 to 150 mm, 1 to 100 mm, 1 to 75mm, 1 to administration of an active drug Substance over a 24 hour 30 60 mm, and 2 to 60 mm. interval. As described above, the pharmaceutical composition may In another specific embodiment, the length of said cylinder comprise a main cylindrical body (also referred to as "cylin part of the matrix (e.g., F in FIG. 11 I-3) or the entire length der part of the matrix”) optionally with one or two tapered of the matrix (e.g., B in FIG.11 I-3) is in a range selected from ends. For example, FIG. 11 I-3 shows one tapered end the 7.5 mm to 15 mm, preferably 7.5 to 10 mm, and 7.5 to 8 mm. 35 length of which is E, the shortest diameter A and the longest along the longitudinal axis. Compositions of these longer diameter C. The length of the tapered end (e.g., E in FIG. 11 lengths are suitable for pharmaceutical compositions formu I-3) may be 0 (i.e., no tapered end) or it may be as long as 40% lated for continued administration of an active drug Substance of the total length, preferably up to 33% of the total length. In Subject to entero-hepatic recirculation over an interval embodiments of the invention wherein the pharmaceutical selected from a range of about 20 to 28 hours, about 22 to 26, 40 composition comprises one or two tapered ends, the total and about 23 to 25 hours. In certain such embodiments, the length of the matrix, including both the cylindrical part of the pharmaceutical composition is formulated and produced for matrix as well as the tapered end(s) (e.g., B in FIG. 11 I-3), continued administration of an active drug Substance over a may be in a range selected from 7.5 to 15 mm, 8 to 15 mm, 8 24 hour interval. to 10 mm, 8.2 to 9.8 mm, 8.4 to 9.6 mm, 8.5 to 9.5 mm, 8.7 to As defined above, the cross section area along an axis, 45 9.3 mm, and 8.9 to 9.1 mm. In specific such embodiments, the preferably the longitudinal axis of said cylinder part of the total length of the matrix, including both the cylindrical part matrix is constant. In one embodiment, the cross sectional of the matrix as well as the tapered end(s), may be selected area of the cylinder part of the matrix is at least 1 mm. For from 9 mm and 9.5 mm along the longitudinal axis. example, in certain embodiments, the cross sectional area of The matrix composition may be surrounded by a coating the cylinder part of the matrix is in a range selected from 1 to 50 having at least one opening exposing at least one Surface of 150 mm, 1 to 100 mm, 1 to 75 mm, 1 to 60 mm, and 2 to said matrix. In particular embodiments, the matrix composi 60 mm. tion may be surrounded by a coating having one opening In another embodiment, the cross section area of the cyl exposing at least one surface of said matrix. In other embodi inder part of the matrix is at least 20 mm. For example, in ments, the matrix composition may be surrounded by a coat certain embodiments, the cross sectional area of the cylinder 55 ing having at two openings exposing at least two Surfaces of part of the matrix is selected from at least 22 mm, at least 24 said matrix. Openings provided in the coating may be posi mm, at least 26 mm, at least 28 mm. In other such embodi tioned at one or both end(s) of said cylindrical matrix, thereby ments, the cross sectional area of the cylinder part of the exposing at least one end of the cylindrical shape to the matrix is in a range selected from 20 to 100 mm. 20 to 75 Surrounding environment. Of course, where a pharmaceutical mm, 20 to 60 mm, 20 to 40 mm, 22 to 100 mm, 22 to 75 60 composition as described herein is provided with a matrix mm, 20 to 60 mm, 22 to 40 mm, 24 to 100 mm, 24 to 75 having a coating that includes two openings, one at each end mm, 24 to 60 mm, 24 to 40 mm, 26 to 100 mm, 26 to 75 of a cylindrical matrix, the pharmaceutical composition mm, 26 to 60 mm, 26 to 40 mm, 28 to 100 mm, 28 to 75 includes two ends of the cylindrical shape exposed to the mm, 28 to 60 mm, 28 to 40 mm. Surrounding environment. In FIG.11 I-3, the diameter of the cross section is indicated 65 The inner Surface of a coating provided over a matrix as C. This embodiment is in particularly useful for composi composition as described herein will have essentially the tions comprising a low load of active drug Substance, Such as same shape (or generally exactly the same shape) as the US 9,023,394 B2 29 30 matrix except that the coating contains, for example, one or b) a coating having one or two openings exposing at least two openings. In particular embodiments, the thickness of the one surface of said matrix, said coating being Substan coating is uniform and thus the coating will have essentially a tially impermeable to an aqueous medium. similar shape as the matrix except that the coating contains, The cross section of these compositions is preferably at for example, one or two openings and that the coating in the 5 least 1 mm. For example, in particular embodiments, the absence of the matrix is hollow. Obviously, the outer diameter cross sectional area of Such compositions may be in a range of the coating will be larger than the outer diameter of the selected from 1 to 150 mm, 1 to 100 mm, 1 to 75 mm, and matrix. The difference in diameter will be dependent on the 20 to 75 mm. Such embodiments can be formulated for thickness of the coating. The thickness of the coating may, for continued administration of an active drug Substance over an 10 interval of time selected from about 5 to 20 hours, about 7 to example, be as shown in FIG. 11 I-3, indicated as G. 20 hours, and about 10 to 20 hours. In certain such embodi It is, however, also contemplated that in other embodi ments, the pharmaceutical composition may be formulated ments, the coating is not uniformly thick and, thus, while the for continued administration of an active drug Substance over inner Surface of the coating will have essentially the same an interval of time selected from about 10 to 18 hours, about shape (or generally exactly the same shape) as the matrix, the 15 10 to 16 hours, about 10 to 14 hours, and about 11 to 13 hours. outer Surface of the coating may have a different shape. In And in one such embodiment, pharmaceutical composition specific Such embodiments, the outer Surface of the coating is, may be formulated for continued administration of an active nevertheless, cylindrical and may take any of the cylindrical drug substance over a 12 hour interval between individual shapes described herein above in relation to the matrix. administrations. The coating (sometimes also referred to as “shell’) may be Thus, the pharmaceutical compositions described herein cylindrical, and in certain embodiments, both the inner Sur may be cylindrical in shape with the two ends exposing the face and the outer Surface of the coating are cylindrical. eroding matrix composition. Such a shape will typically give However, optionally, the coating may furthermore be rounded rise to Zero order release because the releasing area is con at the first end and/or the second end. The coating may also stant. In a specific example, the compositions employed are taper along the longitudinal axis at one or both ends. 25 coated in Such a manner that the Surface has a Substantially As mentioned above, the coating is preferably cylindrical constant or controlled surface area during release or erosion. optionally with tapered ends and it is preferred that the length In the present context, controlled Surface area relates to a of said coating (e.g., B in FIG. 11 I-3) is in a range selected predetermined surface area typically predicted from the from 7.5 mm to 15 mm, 8 to 15 mm, 8 to 10 mm, 8.2 to 9.8 shape of the coat of the unit dosage system. It may have a mm, 8.4 to 9.6 mm, 8.5 to 9.5 mm, 8.7 to 9.3 mm, and 8.9 to 30 simple uniform cylindrical shape or the cylindrical form can 9.1 mm. In one Such embodiment, the length of said coating have one or more tapered ends in order to decrease (or is 9 mm measured along the longitudinal axis of said cylinder. increase) the initial release period. Aforementioned lengths of said coating are in particular rel As yet another example, the release mechanism of dissolv evant for pharmaceutical compositions formulated for con ing/solubilization also depends on the releasing area and the tinued administration of an active drug Substance over a 35 release rate may be controlled by what area of the matrix is period of time ranging from about 20 to about 28 hours, such covered by said coating. In general, the majority of the matrix as those providing continued administration of an active drug is covered by a coating having one or two openings. In Substance over a period of time in a range selected from about embodiments described herein, the sides of the cylindrical 22 to about 26 hours and about 23 to about 25 hours. In once shape (i.e., of the cylindrical matrix) are at least partly cov Such embodiment, pharmaceutical compositions formulated 40 ered by said coating. In specific embodiments, at least 70%, at for continued administration of an active drug Substance over least 80%, at least 90%, at least 95%, or all of the sides of the a period of about 24 hours. cylindrical shape (i.e., of the cylindrical matrix) are covered Therefore in specific embodiments of the pharmaceutical by said coating. One or both ends of the matrix, including compositions described herein, the coating is the same length optionally tapered ends may be partly covered by said coat as the matrix. Thus, by way of example, if the matrix is about 45 ing, or they may be uncovered by any coating. Thus, one or 9 mm, then in Such embodiments, the length of the coating both ends may be exposed to the Surroundings. matches the length of the matrix and is also about 9 mm. In In a particular embodiment, the pharmaceutical composi Some embodiments, wherein the matrix contains one or two tion is prepared for oral intake, preferably for oral intake by tapered ends, then the coating may be shorter than the matrix. Swallowing. Accordingly, the size of the pharmaceutical com In these embodiments, the coating may have the same length 50 position should be in a range that allows oral intake by Swal as the cylindrical part of the matrix, and thus covers the lowing. cylinder part of the matrix leaving the tapered ends exposed. Where the pharmaceutical composition is produced for Pharmaceutical compositions formulated for administra oral administration, the coating or shell has outer dimensions tion more frequent than an interval ranging from about 20 to making the shell suitable for oral administration. The shell about 28 hours between administrations are, in general, 55 may have a length (extension along the first axis, e.g., B in shorter that those formulated and produced to provide admin FIG. 11 I-3) in a range selected from about 7.5 mm to 15 mm istration of an active drug Substance over an interval of about and 8 mm to 10 mm (see above). The shell may have a height 20 to 28 hours. In one aspect, the pharmaceutical composi (extension along the second axis, e.g., the diameter, e.g., D in tions described herein include: FIG. 11 I-3) in a range selected from about 2 mm to 20 mm, a) a matrix composition comprising 60 2 mm to 15 mm, 2 to 10 mm, and 4 to 10 mm. In certain such i) an active drug Substance as described herein; and embodiments, the shell may have a height selected from ii) at least one polyglycol as described herein, approximately 4.5 mm, approximately 5.6 mm, and approxi said matrix composition having a cylindrical shape with mately 8.3 mm. The shell may have a width (extension along optionally tapered end(s), with the length of said matrix the third axis, e.g., diameter, e.g., D in FIG. 11 I-3) in a range being in a range selected from 4 to 8 mm, 5.5 to 8 mm, 6 65 selected from approximately 2 mm to 20 mm, 2 mm to 15 to 7.5 mm, and 6 or 7.5 mm, said matrix being sur mm, 2 to 10 mm, 4 to 10 mm, and 3 to 5 mm. In certain such rounded by embodiments, the shell may have a width selected from US 9,023,394 B2 31 32 approximately 3.4 mm, approximately 4.3 mm, approxi In an embodiment, the coating is one which biodegrades, mately 4.4 mm, approximately 4.5 mm, and approximately disintegrates crumbles or dissolves after erosion of the matrix 4.7 mm. In this context approximately means +/-10%. The and/or during the release of the active drug Substance. In outer surface of the shell may have a double curved surface to particular embodiments, therefore, a coating applied for an facilitate oral administration of a pharmaceutical composi 5 erosion matrix will remain intact as long as it is Supported by tion comprised in the shell. the matrix containing the active drug Substance, but it lacks The opening may have any suitable shape, such as, for the ability to remain intact after erosion of the matrix, because example, circular, oval, rectangular, triangular, angular, it then biodegrades, disintegrates or crumbles, so that it will polygonal or star shaped. The opening may have a shape not remain in, for example, a human for any significant similar to or the same as the cross section of the matrix. In 10 amount of time after the complete erosion of the matrix and specific embodiments, the pharmaceutical compositions the release of the active drug Substance. comprise a matrix Surrounded by a coating having two open In a one embodiment, the shell (coating) may biodegrade, ings, wherein each opening is positioned at each end of said disintegrate, crumble or dissolve after erosion of the matrix matrix and each opening has essentially the same shape as the 15 composition and/or during the release of the active drug Sub cross section of said matrix. For example, in FIG. 11 I-3, one stance in the matrix composition. opening has a diameter of A and the other a diameter of C. It The coating or shell in general comprises or even consist of is also possible that two openings have a diameter of C. An one or more polymers. It is preferred that at least one Such opening may have any Suitable size. Such as an area in a range polymer is a thermoplastic polymer. In some embodiments, selected from about 1 mm to about 150mm, about 1 mm to all polymers included in the shell are thermoplastic polymers. about 100 mm, about 1 mm to about 75 mm, and about 2 Thus, in one embodimentall the polymers used to form the mm to about 65 mm. In one embodiment, the opening has shell (coating) are thermoplastic polymers. As used herein, the same area as the cross sectional area of the cylindrical part “thermoplastic polymers' refers to polymers that are an elas of the matrix. Thus by way of example, in such an embodi tic and flexible liquid when heated and freezes to a solid state ment, if the cross sectional area is in the range of 1 to 75mm, 25 when cooled (e.g., cooled to 20° C. or to ambient tempera then the area of one opening is preferably also in the range of ture). 1 to 75mm and, accordingly, the area of two openings in total The shell (coating) may be made of a material comprising would then be in the range of 2 to 150 mm. Similarly, if the one or more of the polymers described herein in this section. cross sectional area is at least 20 mm, then the area of one For example, the shell may be made of a material comprising opening is also at least 20 mm and, accordingly, the area of 30 two openings in total would then be at least 40 mm. one or more starch based polymers, one or more cellulose Coating based polymers, one or more synthetic polymers, one or more The pharmaceutical compositions according to the inven biodegradable polymers or a combination thereof. Such as tion comprise a matrix Substantially Surrounded by a coating mixtures of starch and synthetic polymers or mixtures of with at least one opening. In certain embodiments, the coating 35 starch and biodegradable polymers. includes one opening. In other embodiments, the coating In some embodiments, the shell (coating) may be made of includes two openings. In further such embodiments, the a material comprising one or more polymers selected from pharmaceutical compositions consist essentially of a matrix the group consisting of Ethyl cellulose grade 20 and 100, Substantially Surrounded by a coating as described herein. polylactic acid (PLA), Cornpack 200, polycaprolactone, PEO The coating may also be referred to as “shell herein and 40 7000000 and polyhydroxybuturate. these terms are used interchangeably. The shape of the shellor Starch Based Polymers coating is described herein above in the section “Geometry”. The shell (coating) may comprise one or more starch based The composition of the shell or coating is described herein polymers. In particular embodiments, the starch based poly below. mer may be starch as such or a polymer having a high starch For the present purpose, the shell or coating is imperme 45 content selected from more than 70% starch, more than 80% able to an aqueous medium, Such as water. This ensures that starch, or more than 90% starch. Starch is a linear polysac the matrix is in contact with Surrounding aqueous media via charide made up of repeating glucose groups with glyco-sidic the one or more openings in the coating. In addition, in par linkages in the 1-4 carbon positions with chain lengths of 500 ticular embodiments, the coating is Substantially insoluble in to 2,000 glucose units. There are two major polymer mol an aqueous medium, and in certain such embodiments, the 50 ecules in starch-amylose and amylopectin. coating is insoluble in an aqueous medium. Starch based polymers that may be used in forming a shell In a specific example, the coating is Substantially insoluble, Suitable for use in pharmaceutical compositions described non-erodible and impermeable to water leaving only the herein may be thermoplastic starch biodegradable plastics exposed areas of the matrix for release. Within the present (TPS). TPS have a starch (amylose) content greater than 70% context, the coating is considered substantially insoluble in an 55 and are, in general, based on gelatinised vegetable starch. aqueous medium if the coating dissolves so much slowerin an Said vegetable starch may for example be selected from the aqueous medium than the matrix composition that the coating group consisting of potato starch, rice starch, maize starch, remains intact until the matrix has eroded and/or released the tapioca starch, wheat starch, dextrin, carrageenan and chito active drug Substance. san. Said vegetable starch may provide Suitable polymers A coating is considered Substantially insoluble in water 60 used in the shell (coating) composition. Starch based poly when it has a solubility in water of at least 100, for example at mers, in general, do not have a specified melting point, but least 1000, wherein solubility is determined as parts of water typically change phase within a temperature range of 90° C. needed to dissolve 1 part of solute at ambient temperature. to 260° C., depending upon the chain length of the starch The coating is considered insoluble in water, when it has a based polymer, water content, and their branching and added solubility in water of at least 10,000, wherein solubility is 65 side-groups as does the degree of crystallinity of the starch. determined as parts of water needed to dissolve 1 part of Long chained-starches are usually completely amorphous, Solute at ambient temperature. while shorter length starches may be semi-crystalline (20 US 9,023,394 B2 33 34 80% crystalline). In specific embodiments relatively long nitrate, methylcellulose, carboxymethylcellulose and salts polymer chains can contribute to the hardness of the shell, thereof, cellulose acetate phthalate, microcrystalline cellu while not being too brittle. lose, ethylhydroxyethylcellulose, ethylmethylcellulose, Starch-based polymers are in general fully biodegradable hydroxyethylcellulose, hydroxyethylmethylcellulose, as they are product of plant materials. The degradation rate hydroxypropylcellulose, hydroxypropylmethylcellulose, varies and can be further induced by addition of other biode hydroxymethylcellulose phthalate, hydroxymethylcellulose gradable polymers as listed herein. and hydroxymethylpropylcellulose, cellulose acetate, cerato One example of a starch based polymer, which may be used nia (high molecular-weight 310 000 daltons). to form the shell or coating described herein is maize starch. Cellulose based polymers are, in general fully, biodegrad Maize starch is a linear polysaccharide made up of repeating 10 able as they preferably are products of plant materials. The glucose groups with glyco-sidic linkages in the 1-4 carbon degradation rate of cellulose based polymers is, in general, positions with chain lengths of 500 to 2,000 glucose units. slower than that of starch based polymers. This degradation There are two major polymer molecules in starch-amylose rate can be induced or increased by addition of other biode and amylopectin. An example of a Suitable maize starch is gradable polymers as listed herein. These other polymers may cornpack. Cornpack is the maize starch used in some 15 be polymers which can be attacked by microorganism which examples described herein below. degrades the shell (coating) composition into Smaller pieces Starch is widely used in the food and pharmaceutical giving rise to a bigger Surface and thereby faster degradation. industries as a binder and diluent. It is edible and essentially In particular embodiments, the coating comprises ethyl nontoxic. Starch is in general cheap and obtains a good hard cellulose C12H2O (C12H22Os), C12H2Os, where n can vary ness when moulded. Starch may, in general, also be reheated to provide a wide variety of molecular weights. Ethylcellu several times without losing its thermodynamic properties. lose, an ethyl ether of cellulose, is a long-chain polymer of Accordingly, in particular embodiments of the pharmaceuti B-anhydroglucose units joined together by acetal linkages. cal compositions described herein, the coating comprises at Ethyl cellulose comes in different grades, which vary in least one starch based polymer, and in certain Such embodi molecular weight and number of ethoxy groups. In certain ments, the coating comprises a starch. Utilization of a starch 25 embodiments, the ethylcellulose is selected from one or more informing the coating compositions may be a great advantage of grades from 20-300, which are commercially available. when applying injection moulding or co-extrusion as a pro Grades with high molecular weights may also be used duction process. because they are optimal to give a hard shell (coating). The Starch based polymers are in general decomposable, and shell (coating) may comprise one or more ethyl celluloses usually have a fast disintegration rate, especially in mixture 30 with different grades. For example, the shell may include a with biodegradable polymers. Starch based polymers are in first ethyl cellulose with a grade selected from a grade ranging generally recognized as stable and inertin solid dosage forms. from 20 to 300, a grade ranging from 20 to 100, a grade Cellulose Based Polymers ranging from 20 to 40, and a grade of 20 and a second ethyl The coating or the shell may also comprise one or more cellulose with a grade selected from a grade ranging from 20 cellulose based polymers. In certain embodiments, the coat 35 to 300, a grade ranging from 50 to 200, a grade ranging from ing may even consist of one or more cellulose based polymers 80 to 120, and a grade of 100. Ethyl cellulose generally has a (such as ethyl cellulose) combined with one or more and glass transition temperature within 129-133°C. These poly plasticizers (such as any of the plasticizers described in this mers are widely used in food and pharmaceutical industry as section below) and UV stabilisers (such as any of the UV coater, stabilizer, matrix former and taste masking and are stabilisers described in this section below). 40 regarded as non toxic Substances. Cellulose based polymers are useful in forming a shell Cellulose based polymers are, in general, derived from (coating) composition because cellulose based polymers, for plant material and may subsequently be modified. Many cel example, ethylcellulose (particularly grade 100-300), fre lulose based polymers are cheap and give a good hardness quently have increased hardness and high ductility. when moulded. As derivatives of plants, cellulose based poly Therefore, in particular embodiments, the coating com 45 mers are in general easily decomposable when disposed. prises a cellulose based polymer which is substantially These polymers are generally stable and inert when incorpo insoluble or is insoluble in an aqueous medium. The cellulose rated in Solid dosage forms. based polymer may be cellulose, wherein one or more of the Synthetic Polymers free —OH groups have been substituted with an R-group to The coating used in a pharmaceutical composition as forma —O—R group. R may in this context, for example, be 50 described herein may also comprise one or more synthetic linear or branched lower alkyl, linear or branched lower alkyl polymers. Suitable synthetic polymers for use in the shell OH, linear or branched lower alkyl-COOH, -CO-(linear or (coating) composition may, for example, be one or more branched lower alkyl), nitrate, aromatic rings or combina selected from polyamide, polyethylene, polyethylene tereph tions of the aforementioned. Lower alkyl is preferably a Co thalate, polypropylene, polyurethane, polyvinyl acetate, alkyl, more preferably C. alkyl. 55 polyvinyl alcohol, polyvinyl butural, polyvinyl chloride), Accordingly, the cellulose based polymer may, for Eudragit L. methyl ester, Eudragit RL, Eudragit RS, Eudragit example, be one or more selected from ethylcellulose, cellu S and Eudragit E, silicone rubber, latex, teflon, copolymers lose acetate, cellulose propionate, cellulose nitrate, methyl such as ethylene vinyl acetate (EVA), styrene-butadienesty cellulose, carboxymethylcellulose and salts thereof, cellulose rene (SBS) and styrene-isoprene-styrene (SIS), Polyethylene acetate phthalate, ethylhydroxyethylcellulose, ethylmethyl 60 glycols, polyvinylpyrrolidone, polyethylene oxide (ranging cellulose, hydroxyethylcellulose, hydroxyethylmethylcellu in molecular weights 100,000 to 8,000,000 daltons), car lose, hydroxypropylcellulose, hydroxypropylmethylcellu boxymethylene (Carbomer) and Sugars thereof (e.g., allylsu lose, hydroxymethylcellulose and crose) and co-polymers of ethylene and propylene oxide hydroxymethylpropylcellulose and cellulose acetate. (PoloXamer). The coating may also comprise one or more cellulose 65 Biodegradable Polymers based polymers selected from cellulose acetate, cellulose Biodegradation is the process by which microorganisms propionate, silicified microcrystalline cellulose, cellulose (microbes such as bacteria, fungi or algae) convert materials US 9,023,394 B2 35 36 into biomass, carbon dioxide and water. Biomass is a general tallinity can be selected and optimized for a particular appli term used to refer to the cells of the microorganisms that are cation. Each degree of crystallinity has different mechanical using the material as a carbon Source. properties, thus, for example, adhesion of the polymer mate The coating used in the pharmaceutical compositions rial to the matrix may vary depending on the degree of crys described herein may also comprise one or more biodegrad 5 tallinity of the given material (PLA). able polymers. Said biodegradable polymer(s) may be one or The skeletal structure of PLA is shown below. more selected from starch based polymers as described herein above in this section and cellulose based polymers as described herein above in this section. The biodegradable polymer may also be one or more selected from polyhydroxy 10 butyrate(PHB), polyhydroxyvalerate(PHV), polyhydroxy Valerate-co-hydroxyvalerate(PHV/VH), Polyhydroxyal kanoates(PHA), poly-3-hydroxy-5-phenylvalerate (PHPV), aliphatic polyesters, polycaprolactone(PCL), polylactic acid has (PLA), polyglycolic acid (PGA), copolymers or block 15 copolymers of polycaprolactone(PCL), polylactic acid (PLA) Due to the chiral nature of lactic acid, several distinct forms and/or polyglycolic acid(PGA), poly-propylene carbonate of polylactide exist: poly-L-lactide (PLA in its L-form), (PPC), polyester amide (PEA), polybutylene succinate adi referred to as PLLA, is the product resulting from polymer pate (PBSA), polybutylene adipate co-terephtalate (PBAT) ization of L.L-lactide (also known as L-lactide), and poly-D- and polybutylene succinate-adipate (PESA). lactide (PLA in its D-form) referred to as PDLA is the product Copolymers or block copolymers of polycaprolactone resulting from polymerization of L,L-lactide (also known as (PCL), polylactic acid (PLA) and/or polyglycolic acid (PGA) L-lactide). Furthermore, PLLA and PDLA may be mixed may, for example, be selected from poly(lactic-co-glycolic with various ratios of the two stereo forms. The L-form gen acid)(PLGA), polylactic acid and epsilon-caprolactone erally has more robust mechanical properties than the D-form copolymer(PLA/CL) and polylactic acid/glycolic acid poly 25 and the L-form has been typically used in pharmaceutical mers)(PLA/GA), which are all commercially available. products. In order to achieve mechanical or other properties In one embodiment, the coating comprises one or more that may not be obtained through use of a D-form or L-form biodegradable polymers selected from polylactic acid (PLA), alone, targeted properties of a shell (coating) may, in some polycaprolactone (PCL) and polyhydroxybutyrate (PHB), embodiments, be achieved by blending the D-form to the preferably the coating comprises both polylactic acid (PLA), 30 L-form. For example, in some such embodiments, the D-form polycaprolactone (PCL) and polyhydroxybutyrate (PHB). may be added to the L-form in amounts of 5, 10, 20, 30, 40% The use of polycaprolactone and other polymers in this wfw, up to a ratio of 1:1. Blending of the D-form with the group has been increased over the last decade, while the L-Form may result in a completely amorphous material or, demand for environmental friendly plastics has grown. These alternatively, Such blending may also form a highly regular polymers are regarded as nontoxic and are already used in 35 Stereo complex with increased crystallinity, since addition of parenteral pharmaceutical formulations. Such polymers can PDLA increases the molecular energy of the mixture by form facilitate formulation of a more flexible shell (coating) when ing a concentration gradient. PLA in its L-form has a crystal moulded in mixture with starch derived polymers. The some linity of around 35-45%, a glass transition temperature what rigid structure of pure thermoplastic starch may be between 35-80° C. and a melting temperature between 173 adjusted as desired by inclusion polycaprolactone or other 40 1780 C. biodegradable polymers disclosed herein. Furthermore the Due to the structure of PLA, PLA may be exposed to biodegradable polymers are decomposable and disintegrate hydrolysis during its path through the gastro-intestinal tract. by microorganisms. However PLA is impermeable and insoluble in aqueous Polylactic Acid media, and in relation to applying PLA as shell (coating) Polylactic acid or polylactide (PLA) may be used in form 45 material, shells (coatings) formed using PLA, at least macro ing the coatings included in the pharmaceutical compositions scopically, have proven to remain intact within the first 48 described herein. PLA is biodegradable, thermoplastic, ali hours of exposure. Furthermore, the possible degradation phatic polyester derived from renewable resources, such as product of PLA is merely lactic acid. corn starch. PLA belongs to the chemical family of polyes Polyglycols ters, such as, for example, e-caprolactone, PLA-caprolactone 50 The coating used in the pharmaceutical compositions in different ratios 15% PLA to 100% (25, 35, 50, 75, 85%), described herein may also comprise any of the above-men polyglycolides, polyglycolic acids (PGA), poly(lactide-co tioned polyglycols in a form, which erodes at a Substantially glycolide) in different ratios 15 to 100% PLA (25,35, 50, 75, slower rate than the matrix composition. The coating may 85%), poly(lactide-co-glycolide)-OH in different ratios 15% thus be one which is eroded in an aqueous medium at a PLA to 100% (25, 35, 50, 75, 85%). Each of the before 55 Substantially slower rate than the matrix composition com mentioned polymers exist in Lor D-form (making them opti prising the active drug Substance, whereby a Substantially cally active) and in equal amounts (1:1) of L- and D-forms controlled area of the matrix composition comprising the results in an amorphous mixture, while the L- or D-forms active drug Substance is exposed during erosion and/or possess a certain degree of crystallinity. The degree of crys release of the matrix composition, and whereby the coating is tallinity is related to the mechanical properties (including 60 Substantially eroded upon erosion and/or release of the matrix processability) and physico-chemical properties, such as sta composition comprising the active drug Substance. Such a bility, of the polymer. The form and level of crystallinity or coating may be designed so that its longitudinal erosion rate extent of amorphous characteristics of Such polymers can is substantially the same as the longitudinal erosion and/or therefore be selected to enhance one or more of processabil release rate of the matrix, whereby the matrix and the coating ity, mechanical attributes of the pharmaceutical composition, 65 will erode longitudinally towards the centre of the composi or stability of an active drug Substance or the pharmaceutical tion at Substantially the same rate. Thus, in Such embodi composition itself. Therefore, with PLA, the degree of crys ments, when the matrix composition has been completely US 9,023,394 B2 37 38 eroded and/or released by the aqueous medium, the coating example comprise a mixture of PLA and ethylcellulose. In a will also be substantially completely eroded. A matrix com specific embodiment, the coating consists of PLA, ethyl cel position having Such a coating has the advantage of being lulose, one or more plasticizers (such as any of the plasticizers completely biodegraded upon release of the active drug Sub described herein below) and one or more UV stabilisers (such Stance. as any of the UV stabilisers described herein below). A polyglycol Suitable for inclusion in a coating used in a UV Stabiliser pharmaceutical composition as described herein is high Radiation from Sunlight can accelerate the degradation of molecular weight PEO, such as a PEO with an average plastics, such as the shell (coating) described herein. The molecular weight which is significantly higher than the aver packaging material to protect the pharmaceutical composi age molecular weight of any of the PEOs contained in the 10 tions (e.g., tablets) from direct Sunlight may not be enough matrix composition. Thus, for any given pharmaceutical protection. Especially for a shell (coating) with high concen composition it is preferred that any PEO contained in the shell tration of biodegradable polymers, it may be useful to add (coating) has a significantly higher average molecular weight UV-stabilizers to the compositions, due to many unsaturated than any PEO contained in the matrix. Accordingly, where the functional groups (e.g., carbonyl groups). UV-stabilizers may coating comprises one or more PEO, in certain embodiments, 15 be, selected from, for example, titanium dioxide, metal com the average molecular weight of the PEO may be selected plexes with Sulfur containing groups, hindered amine light from at least 900,000 daltons, at least 2,000,000 daltons, at stabilisers (HALS), benzophenones, benzotriazoles. Tita least 4,000,000 daltons, and at least 6,000,000 daltons. In a nium dioxide is already widely used in pharmaceutical prepa particular embodiment, the coating includes a PEO having a rations as pigment and is considered non toxic. molecular weight of about 7,000,000 daltons. Plasticizer Mixtures of Polymers In addition to above mentioned polymers, the coating may As noted herein above the coating may comprise one or comprise one or more additional components. Thus, the coat more different polymers. In some embodiments, the coating ing may comprise at least one selected from the group con may comprise one or more different polymers selected from sisting of starch based polymers, cellulose based polymers, synthetic 25 i) polymers which are soluble or dispersible in water, polymers and biodegradable polymers described herein. ii) plasticizers, and In one embodiment, the coating comprises polymers iii) fillers selected from starch based polymers and biodegradable poly in some embodiments the polymers, which are soluble or mers. In one Such embodiment the polymers may be selected dispersible in water, are cellulose derivatives, which are from any of the starch based polymers and biodegradable 30 soluble or dispersible in water. Thus, the shell (coating) mate polymers described herein above in this section. In particular, rial may comprise one or more plasticizers, preferably, any of biodegradable polymers such as polycaprolactone, polyhy the plasticizers described herein above in the section “phar droxybuturate, polyhydroxyvalerate, polylactic acid, polyhy maceutically acceptable excipients' and/or any of the plasti droxyalkanoates and/or polypropylenecarbonate can be cizers described below. Where a plasticizer is included, the blended with various starches (such as any of the starches 35 shell (coating) material may include one or more of the fol described herein above in this section) in different ratios. lowing plasticizers: Cetostearyl alcohol, castor oil, dibutyl Suitable mixtures for use in the shell (coating) composition sebacate, polyethylene oxides and/or PoloXamer. However are, for example, polycaprolactone and Sago and/or cassava other plasticizers may also be used to provide desired material starch, polycaprolactone or polyhydroxybuturate and pre properties. dried, thermoplastic starch, polycaprolactone and gelatinized 40 Other suitable plasticizers may be selected from mono- and starch or thermoplastic starch. Other suitable mixtures di-acetylated monoglycerides, diacetylated monoglycerides, include starch-based blends with biodegradable thermoplas acetylated hydrogenated cottonseed glyceride, glyceryl tic components like polyester amide, polyhydroxybuturate cocoate, Polyethylene glycols or polyethylene oxides (e.g., co-Valerate or polybutylene Succinate-adipate. Polymers with a molecular weight of about 1,000-500,000 daltons), starches can be cross-linked with Maleic anhydride (MA) and 45 dipropylene glycol salicylate glycerin, fatty acids and esters, dicumyl peroxide (DCP) giving harder items when moulded. phthalate esters, phosphate esters, amides, diocyl phthalate, In another embodiment, the coating may comprise poly phthalylglycolate, mineral oils, hydrogenated vegetable oils, mers selected from Starch based polymer and synthetic poly Vegetable oils, acetylated hydrogenated Soybean oil glycer mers. In particular such embodiments, the coating comprises ides, Castor oil, acetyl tributyl citrate, acetyl triethylcitrate, polymers selected from any of the starch based polymers and 50 methyl abietate, nitrobenzene, carbon disulfide, B-naphtyl synthetic polymers described herein above in this section. salicylate, sorbitol, sorbitol glyceryl tricitrate, fatty alcohols, Suitable mixtures for use in the shell (coating) composition cetostearyl alcohol, cetyl alcohol, Stearyl alcohol, oleyl alco include, for example, native granular starch, modified Starch, hol, myristyl alcohol. Sucrose octaacetate, alfa-tocopheryl plasticized starch blended or grafted with many synthetic polyethylene glycol succinate (TPGS), tocopheryl derivative, polymers such as polyethylene, polystyrene, Purified Tereph 55 diacetylated monoglycerides, diethylene glycol monostear thalic acid (PTA), optionally in mixture with aliphatic poly ate, ethylene glycol monostearate, glyceryl monooleate, esters or polyvinyl alcohols in different ratios. Polybutylene glyceryl monostearate, propylene glycol monostearate, mac succinate (PBS), polybutylene succinate adipate in blend rogol esters, macrogol Stearate 400, macrogol Stearate 2000, with various starches in different ratios are also suitable such polyoxyethylene 50 Stearate, macrogol ethers, cetomacrogol as, for example, Polybutylene succinate in mixture with ther 60 1000, lauromacrogols, nonoxinols, octocinols, tyloxapol, moplastic starch, and alkylene oxide modified Starches in poloxamers, polyvinyl alcohols, polysorbate 20, polysorbate combination with hydrolyzed polyvinyl alcohol. 40, polysorbate 60, polysorbate 65, polysorbate 80, polysor In yet another embodiment, the coating may comprise bate 85, sorbitan monolaurate, sorbitan monooleate, sorbitan polymers selected from cellulose based polymers and biode monopalmitate, Sorbitan monostearate, Sorbitan sesqui gradable polymers, such as, for example, any of the cellulose 65 oleate, Sorbitan trioleate, Sorbitan tristearate and Sucrose based polymers and biodegradable polymers described esters, amyl oleate, butyl oleate, butyl stearate, diethylene herein above in this section. Thus, the coating may for glycol monolaurate, glycerol tributyrate, Flexol B-400, US 9,023,394 B2 39 40 monomeric polyethylene ester, Piccolastic A-5, Piccalastic provide an elegant and palatable tablet and/or to easy distin A-25, Clorafin 40, acetyl tributyl citrate, acetyl triethyl cit guishable dose strengths. It can be particularly useful to coat rate, benzyl benzoate, butoxyethyl Stearate, butyl and glycol compositions having different dose strengths or active drug esters of fatty acids, butyl diglycol carbonate, butyl ricino substances with outer coats of different colours so that the leate, butyl phthalyl butyl glycolate, camphor, dibutyl seba 5 different actives and dose strengths are easily distinguished. cate, dibutyl tartrate, diphenyl oxide, glycerine, HB-40, Where provided, the outer coat will typically be easily soluble hydrogenated methyl ester of rosin, methoxyethyl oleate, in aqueous media in order to facilitate contact of the matrix monoamylphthalate, Nevillac 10, Paracril 26, technical composition with the Surrounding aqueous media via the hydroabietyl alcohol, triethylene glycol dipelargonate, Solid openings in the coating rapidly after administration. aliphatic alcohols and mixtures thereof. 10 Pharmaceutical Compositions In certain embodiments, the shell (coating) is made of a In particular embodiments, pharmaceutical compositions material, wherein the concentration of plasticizer is from 0 to as described herein comprise: an active drug selected from 30% w/w. In particular such embodiments, the shell com oxycodone, hydrocodone, hydromorphone, norhydrocor prises one or more plasticizer(s) and one or more polymer(s). done, oxymorphone, noroxycodone, morphine, morphine-6- In further such embodiments, the shell consists essentially of 15 one or more plasticizer(s) and one or more polymer(s). glucuronode and pharmaceutically acceptable salts thereof, Furthermore, the coating may comprise Sweetening agents, Such as morphine Sulphate, morphine Sulphate pentahydrate, flavouring agents and/or colouring agents, which may be any oxycodone hydrochloride, hydrocodone bitartrate and hydro of the Sweetening agents, flavouring agents and/or colouring morphone hydrochloride; at least one polyglycol selected agents described herein above in the section “pharmaceuti from polyethyleneglycol and polyethylene oxide and any cally acceptable excipients’. mixtures thereof, and a coating comprising (i) a material In particular embodiments, the shell (coating) may be selected from ethyl cellulose, polylactic acid, polycaprolac made of a material comprising a single polymer material, and tone, polyhydroxybutyrate and polyethylene oxide and any wherein the concentration of the polymer is from 5 to 100% mixtures thereof, (ii) a plasticizer selected from the group wfw. 25 consisting of poloxamer, polyethylene oxide, cetostearyl In other embodiments, the shell (coating) may be made of alcohol, castor oil and dibutyl sebacate and any mixtures a material comprising a mixture of polymers, and wherein the thereof, and (iii) a filler, which is titanium dioxide. total concentration of polymers is from 70 to 100% w/w. In further embodiments, pharmaceutical compositions as In yet further embodiments, the coating comprises an described herein comprise: an active drug selected from mor amount of one or more polymers selected from at least 50% 30 phine, oxycodone, hydrocodone, hydromorphone, norhydro w/w, at least 60% w/w, at least 70% w/w, and at least 80% cordone, oxymorphone, noroxycodone, morphine-6-glucu w/w, wherein said one or more polymers are substantially ronode and pharmaceutically acceptable salts thereof, such as insoluble in water as described herein above. morphine Sulphate, morphine Sulphate pentahydrate, oxyc Thus, in specific embodiments, wherein the coating com odone hydrochloride, hydrocodone bitartrate and hydromor prises cellulose derivatives (such as ethyl cellulose), then the 35 phone hydrochloride; at least one polyglycol selected from coating may comprise cellulose derivatives in an amount polyethyleneglycol and polyethylene oxide and any mixtures selected from at least 50% w/w, at least 60% w/w, at least 70% thereof; at least one plasticizer which is poloxamer; at least wfw, at least 80% w/w, at least 85% w/w. In one such embodi one stabilizer selected from mannitol, butylated hydroxytolu ment, the coating comprises 87% w/w of a cellulose deriva ene and Vitamin E Polyethylene Glycol Succinate, Eudragit tive polymer material (Such as ethyl cellulose). 40 L., Eudragit RL, Eudragit RS, Eudragit E. Eudragit S, and at In certain embodiments, the coating comprises an amount least one gelling agent selected from the group consisting of of plasticizer selected from at the most 19% w/w, at the most carrageenan and hydroxypropylmethylcellulose; and a coat 15% w/w, and at the most 12% w/w. In one such embodiment, ing material comprising (i) a material selected from ethyl the coating comprises at the most 12% W/w plasticizer (Such cellulose, polylactic acid, polycaprolactone and polyethylene as cetostearyl alcohol). 45 oxide and any mixtures thereof, (ii) a plasticizer selected from In still further embodiments, wherein the coating com polyethylene oxide and cetostearyl alcohol and any mixtures prises biodegradable polymers (such as polylactic acid), then thereof, and (iii) a filler, which is titanium dioxide. the coating may include the biodegradable polymer material In cases where the pharmaceutical composition also com in an amont selected from at least 50% w/w, at least 60% w/w, prises an outer coat, in specific embodiments, the pharmaceu at least 70% w/w, at least 80% w/w, and at least 85% w/w. In 50 tical composition as described herein may comprise: an active one such embodiment, the coating comprises 86% w/w bio drug Substance selected from morphine, oxycodone, hydro degradable polymer material (Such as polylactic acid). codone, hydromorphone, norhydrocordone, oxymorphone, In S additional embodiments, the coating comprises an noroxycodone, morphine-6-glucuronode and pharmaceuti amount of plasticizer selected from at the most 20% w/w, at cally acceptable salts thereof. Such as morphine Sulphate, the most 17% w/w, and at the most 15% w/w. In one such 55 morphine Sulphate pentahydrate, oxycodone hydrochloride, embodiment, the coating comprises 14% w/w plasticizer hydrocodone bitartrate and hydromorphone hydrochloride; (polyethylene oxides 200,000 daltons). at least one polyglycol selected from polyethyleneglycol and Outer Coat polyethylene oxide and any mixtures thereof, and a coating In some cases the pharmaceutical composition of the comprising (i) a material selected from ethyl cellulose, poly present invention may also comprise an outer coat that fully 60 lactic acid, polycaprolactone, polyhydroxy butyrate and covers the pharmaceutical composition (fully covers both the polyethylene oxide, and any mixtures thereof, (ii) a plasti matrix composition and the coating or shell). Said outer coat cizer selected from poloxamer, polyethylene oxide, ceto may be selected from the group consisting of task masking Stearyl alcohol, castor oil and dibutyl sebacate and any mix coats, coats with aqueous moisture barriers and/or oxidative tures thereof, and (iii) a filler, which is titanium dioxide; and barriers to improve the stability of the composition, and cos 65 an outer coat selected from task masking coats, coats with metic coats, such as, for example, a coat containing colouring aqueous moisture barriers and/or oxidative barriers, cosmetic agents, Sweetening agents and/or flavouring agents in order to coats, and any mixtures thereof. US 9,023,394 B2 41 42 In a specific embodiment the pharmaceutical composition In yet another embodiment, the pharmaceutical composi includes a matrix composition comprising morphine Sulphate tion includes a matrix composition comprising hydrocodone as the active drug Substance, a mixture of polyethylene oxide bitartrate as the active drug, a mixture of polyethylene oxide 200,000 and polyethylene oxide 300,000 as polyglycols, 200,000 and polyethylene oxide 300,000 as polyglycols, poloxameras a plasticizer, mannitol as a stabilizer, a mixture poloxameras a plasticizer, and butylated hydroxytoluene as of carrageenan and hydroxypropylmethylcellulose as gelling an antioxidant and a coating disposed over the matrix com agents, and butylated hydroxytoluene as antioxidant and a position comprising a mixture of polylactic acid and polyeth coating disposed over the matrix composition comprising a ylene oxide. mixture of polylactic acid and polyethylene oxide. In another embodiment, the pharmaceutical composition In another specific embodiment the pharmaceutical com 10 includes a matrix composition comprising hydrocodone position comprises a matrix composition that comprises mor bitartrate as the active drug, a mixture of polyethylene oxide phine Sulphate as the active drug, a mixture of polyethylene 200,000 and polyethylene oxide 300,000 as polyglycols, oxide 200,000 and polyethylene oxide 300,000 as polygly poloxameras a plasticizer, and butylated hydroxytoluene as a cols, poloxameras a plasticizer, mannitol as a stabilizer, and stabilizer and a coating disposed over the matrix composition butylated hydroxytoluene as an antioxidant and a coating 15 comprising a mixture of ethylcellulose, cetostearyl alcohol disposed over the matrix composition comprising a mixture and titanium dioxide. of polylactic acid and polyethylene oxide. In another embodiment the pharmaceutical composition In yet another specific embodiment, the pharmaceutical includes a matrix composition comprising hydromorphone composition comprises a matrix composition comprising hydrochloride as the active drug, a mixture of polyethylene morphine Sulphate as the active drug, polyethylene oxide oxide 200,000 and polyethylene oxide 300,000 as polygly 300,000 as a polyglycol, poloxamer as a plasticizer, and a cols, poloxameras a plasticizer, hydroxypropylmethylcellu mixture of mannitol and butylated hydroxytoluene as stabi lose as a gelling agent, and butylated hydroxytoluene as an lizers and a coating disposed over the matrix composition antioxidant and a coating disposed over the matrix composi comprising a mixture of ethylcellulose, cetostearyl alcohol 25 tion comprising a mixture of polylactic acid and polyethylene and titanium dioxide. oxide. In still another specific embodiment, the pharmaceutical In another embodiment the pharmaceutical composition composition includes a matrix composition comprising mor includes a matrix composition comprising hydromorphone phine sulphate as the active drug, polyethylene oxide 200,000 hydrochloride as the active drug, a mixture of polyethylene as a polyglycol, and a mixture of mannitol and Vitamin E 30 oxide 200,000 and polyethylene oxide 300,000 as polygly Polyethylene Glycol Succinate as stabilizers and a coating cols, poloxamer as a plasticizer, and butylated hydroxytolu disposed over the matrix composition comprising a mixture ene as an antioxidant and a coating disposed over the matrix of ethylcellulose, cetostearyl alcohol and titanium dioxide. composition comprising a mixture of polylactic acid and In another specific embodiment the pharmaceutical com polyethylene oxide. position includes a matrix composition comprising oxyc 35 In still another embodiment, the pharmaceutical composi odone hydrochloride as the active drug, a mixture of polyeth tion includes a matrix composition comprising hydromor ylene oxide 200,000 and polyethylene oxide 300,000 as phone hydrochloride as the active drug, a mixture of polyeth polyglycols, poloxameras a plasticizer, Eudragit as a stabi ylene oxide 200,000 and polyethylene oxide 300,000 as lizer, hydroxypropylmethylcellulose as a gelling agent, and polyglycols, poloxamer as a plasticizer, and butylated butylated hydroxytoluene as an antioxidant and a coating 40 hydroxytoluene as an antioxidant and a coating disposed over disposed over the matrix composition comprising a mixture the matrix composition comprising a mixture of ethylcellu of polylactic acid and polyethylene oxide. lose, cetostearyl alcohol and titanium dioxide. In another embodiment, the pharmaceutical composition Administration includes a matrix composition comprising oxycodone hydro The pharmaceutical composition according to the inven chloride as the active drug, a mixture of polyethylene oxide 45 tion can be designed for oral administration. For example, the 200,000 and polyethylene oxide 300,000 as polyglycols, pharmaceutical compositions described herein may be pro poloxameras a plasticizer, Eudragit as a stabilizer, and buty duced as unit dosage forms, such as, for example, tablets, for lated hydroxytoluene as an antioxidant and a coating dis oral intake by Swallowing one or more intact units of the posed over the matrix composition comprising a mixture of pharmaceutical composition. polylactic acid and polyethylene oxide. 50 Due to the possibility of controlling the release profile of In yet another embodiment, the pharmaceutical composi the active drug Substance, the pharmaceutical composition tion includes a matrix composition comprising oxycodone may be adapted for oral administration 1-6 times a day, nor hydrochloride as the active drug, a mixture of polyethylene mally 1-4 times daily, Such as 1-3 times, 1-2 times or 1 time oxide 200,000 and polyethylene oxide 300,000 as polygly daily. In one such embodiment, a pharmaceutical composi cols, poloxameras a plasticizer, Eudragit as a stabilizer, and 55 tion as described herein comprising one or more unit dosage butylated hydroxytoluene as an antioxidant and a coating forms, is administered once or twice daily. In yet another disposed over the matrix composition comprising a mixture embodiment, a pharmaceutical composition as described of ethylcellulose, cetostearyl alcohol and titanium dioxide. herein comprising one or more unit dosage forms is admin In still another embodiment the pharmaceutical composi istered once daily. tion includes a matrix composition comprising hydrocodone 60 In one embodiment, the pharmaceutical composition is bitartrate as the active drug, a mixture of polyethylene oxide prepared in unit dosage forms, such that a desired dose of the 200,000 and polyethylene oxide 300,000 as polyglycols, active drug Substance is included within one unit dosage poloxameras a plasticizer, hydroxypropylmethylcellulose as form, wherein the dose is selected for administration with an a gelling agent, and butylated hydroxytoluene as an antioxi interval of in the range of about 20 to 28 hours, such as a 24 dant and a coating disposed over the matrix composition 65 hour interval. The pharmaceutical composition may, in cer comprising a mixture of polylactic acid and polyethylene tain embodiments, be in the form of tablets. In specific such oxide. embodiments, each tablet may comprise one dose of the US 9,023,394 B2 43 44 active drug Substance, wherein the dose is selected for admin position includes morphine or a pharmaceutically acceptable istration at an interval of in the range of about 20 to 28 hours, salt thereof as an active drug Substance and the daily dosage Such as a 24 hour interval. of morphine or a pharmaceutically acceptable salt thereof is Furthermore, the pharmaceutical compositions described selected from 15, 20, 30.45, 60, 75,90, 100, 120, 140, 160, herein may be prepared for continued administration, 5 180 or 200 mg. wherein dosages are preferably administered with an interval In particular, when the active drug Substance included in of in the range of about 20 to about 28 hours, such as about 24 the pharmaceutical compositions is an opioid, and more par hours. The pharmaceutical compositions described herein ticularly, when the active drug Substance is oxycodone or a can be prepared to deliver clinically effective amounts of pharmaceutically acceptable salt thereof, then, in specific active drug Substance for at least 24 hours after intake. In 10 embodiments, the daily dosage may be selected from a range particular embodiments, wherein the pharmaceutical compo of 1 to 1000 mg, a range of 10 to 1000 mg, a range of 30 to sitions are for treatment of pain, then the pharmaceutical 1000 mg, a range of 10 to 500 mg, a range of 10 to 250 mg, a compositions may beformulated to relieve orameliorate pain range of 10 to 200 mg, a range of 10 to 50, a range of 10 to 500 for a period of time selected from 20, 22, 24, 26, and 28 hours mg, a range of 10 to 160 mg, a range of 10 to 100 mg, a range after intake. In one such embodiment, pharmaceutical com 15 of 10 to 80 mg, a range of 20 to 80 mg, a range of 40 to 80 mg. positions as described herein for treatment of pain, and are and a range of 30 to 50 mg. In certain such embodiments, the formulated to relieve or ameliorate pain for at least 24 hours pharmaceutical composition includes oxycodone or a phar after intake. maceutically acceptable salt thereof as an active drug Sub Pharmaceutical compositions as described herein are, in stance and the daily dosage of oxycodone or a pharmaceuti specific embodiments, prepared for continued administra cally acceptable salt thereof is selected from 10, 15, 20, 30, 40 tion, and accordingly, the composition is prepared for 50, 60, 70, 80,90, 100 or 160 mg. repeated administration with an interval of in the range of In particular, when the active drug Substance included in about 20 to about 28 hours, such as about 24 hours between the pharmaceutical compositions is an opioid, and more par administrations. In such embodiments, the continued admin ticularly, when the active drug Substance is hydrocodone or a istration may be administration over several days. In particu 25 pharmaceutically acceptable salt thereof, then, in specific lar embodiments, administration of the pharmaceutical com embodiments, the daily dosage may be selected from a range positions may take place over a period of time selected from of 1 to 1000 mg, a range of 10 to 1000 mg, a range of 15 to at least 3 days, at least 4 days, at least 5 days, at least 6 days, 1000 mg, a range of 1 to 750 mg, a range of 1 to 500 mg, a at least 7 days, at least 9 days, at least 11 days, at least 14 days, range of 1 to 250 mg, a range of 1 to 100 mg, a range of 1 to and at least 30 days, wherein the pharmaceutical composition 30 30 mg, a range of 10 to 500 mg, a range of 10 to 200 mg, a is continuously administered at intervals in the range of about range of 10 to 160 mg, a range of 10 to 30 mg, a range of 20 20 to 28 hours, such as a 24hour interval. In one such embodi to 160 mg, and a range of 20 to 80 mg. In certain such ment, the pharmaceutical composition is administered to a embodiments, the pharmaceutical composition includes patient in need thereof at intervals of about 20 to about 28 hydrocodone or a pharmaceutically acceptable Salt thereof as hours, such as about 24 hour intervals, over a period of time 35 an active drug Substance and the daily dosage of hydrocodone selected from at least 3 days, at least 4 days, at least 5 days, at or a pharmaceutically acceptable salt thereof is selected from least 6 days, at least 7 days, at least 9 days, at least 11 days, at 10, 2030, 40, 50, 60, 70, 80, 100, 120, 140, 160 mg. least 14 days, and for at least 30 days. Continued administra In particular, when the active drug Substance included in tion may be carried out over a period of time that is at least the pharmaceutical compositions is an opioid, and more par sufficient to arrive at steady state in the individual to whom 40 ticularly, when the active drug Substance is hydromorphone the pharmaceutical composition of the invention is being ora pharmaceutically acceptable salt thereof, then, in specific administered. embodiments, the daily dosage may be selected from a range The pharmaceutical compositions described herein can be of 1 to 1000 mg, a range of 1 to 500 mg, a range of 1 to 250 mg. prepared for delivery of desired dosage active drug Substance. a range of 1 to 100 mg, a range of 2 to 250 mg, a range of 2 to The dosage will be dependent on the individual to whom the 45 100 mg, a range of 4 to 100 mg, a range of 4 to 80 mg, and a pharmaceutical composition of the invention is being admin range of 4 to 64 mg. In certain such embodiments, the phar istered and the active drug Substance. maceutical composition includes hydromorphone or a phar In particular embodiments, the dosage for each adminis maceutically acceptable salt thereof as an active drug Sub tration, wherein dosages are prepared for administration with stance and the daily dosage of hydromorphone or a an interval of in the range of about 20 to 28 hours, such as a 24 50 pharmaceutically acceptable salt thereof is selected from 2, 4, hour interval, is in the range of 1 to 1000 mg, such as in the 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 40, 48, 56,64, 72 or 80 range of 10 to 1000 mg, for example in the range of 30 to 1000 ng. mg, Such as in the range of 1 to 750 mg, for example in the Above-mentioned dosages are in particular relevant when range of 1 to 500 mg. Such as in the range of 1 to 250 mg. In the individual in need of treatment is a human being, Such as certain such embodiments, the dosage for each administra 55 an adult human being. tion is in a range selected from 10 to 500 mg and 10 to 240 mg Individuals in Need of Treatment of an active drug Substance. The pharmaceutical composition of the invention is pre In particular, when the active drug Substance included in pared for administration to an individual in need thereof. Said the pharmaceutical compositions is an opioid, and more par individual may be a mammal, and in specific embodiments ticularly, when the active drug Substance is morphine or a 60 the individual is a human being. pharmaceutically acceptable salt thereof, then, in specific In certain embodiments, the pharmaceutical composition embodiments, the daily dosage may be selected from a range is for continuous treatment of pain and accordingly, the indi of 1 to 1000 mg, a range of 10 to 1000 mg, a range of 15 to vidual in need of treatment is an individual suffering from 1000 mg, a range of 1 to 750 mg, a range of 1 to 500 mg, a pain. In particular Such embodiments, the individual is an range of 1 to 250 mg, a range of 10 to 500 mg, a range of 15 65 individual Suffering from pain for a prolonged period of time to 240 mg, a range of 15 to 200 mg, and a range of 30 to 200 requiring continuous treatment, wherein continuous treat mg. In certain such embodiments, the pharmaceutical com ment is as described herein. US 9,023,394 B2 45 46 In embodiments of the invention, wherein the active drug for a sufficient amount of time to reach steady state. However, Substance is an opioid, such as oxycodone, hydrocodone, theoretical steady State parameters may be determined by a morphine or pharmaceutically acceptable salts thereof, then simulation based on information on serum concentration of the pharmaceutical compositions are Suitable for treatment of an active drug Substance or its metabolites after a single moderate to severe pain such as severe pain. 5 administration. Such a simulation may for example be pre Examples of individuals, who may benefit from treatment pared as described in Example 1 or Example 2 herein below. with the pharmaceutical compositions according to the inven Thus, in Some embodiments, the pharmaceutical compo tion include, for example, the following: sitions described herein have a length in a range selected from The individual may be an individual suffering from chronic 7.5 to 15 mm and 8 to 10 mm, said compositions comprise an pain, such as moderate to severe chronic pain; 10 active drug Substance (e.g., an analgesic. Such as an opioid, The individual may be an individual suffering from cancer for example morphine, oxycodone or hydrocodone) and the pharmaceutical composition may be useful for con described herein, and upon administration, the pharmaceuti tinuous treatment of pain or even moderate to severe pain, cal compositions, provide an average steady state trough Such as severe pain in an individual Suffering from cancer, (such as the theoretical steady state trough) of the active drug The individual may also be an individual who has suffered 15 substance selected from at least 30%, at least 35%, and at least a moderate to severe injury; 40% of the average steady state C of the active drug Sub The individual may be an individual suffering from pain stance. In certain such embodiments, upon administration, associated with Surgical conditions, such as a pre-Surgical the pharmaceutical compositions, provide an average steady individual (an individual in need of Surgery) or a post Surgical state trough of the active drug Substance selected from a range individual (an individual who has undergone Surgery); of 30% to 80%, a range of 35 to 80%, and a range of 40 to 80% The individual may also be an individual suffering from or of the average steady state C of the active drug substance. having Suffered from a myocardial infarction, sickle cell cri Again, in Such embodiments, the active drug Substance ses, kidney Stone or severe back pain; maybe an opioid such as those described herein. In one Such The individual may also be an individual suffering from embodiment, the opioid is hydrocodone or a pharmaceuti degenerative pain, herniated disc pain, fibromyalgia, neuro 25 cally acceptable salt thereof. pathic pain and/or nociceptive pain; and In some embodiments, the pharmaceutical compositions The individual may also be an individual suffering from described herein have a length in a range selected from 7.5 to arthritis, such as arthritis osteo, arthritis rheumatoid, arthritis 15 mm and 8 to 10 mm, said compositions comprise an active psoriatica and/or arthritis urica. drug Substance (for example, an analgesic, such as an opioid, Pharmacokinetics 30 for example morphine, oxycodone or hydrocodone) The pharmaceutical compositions described herein are described herein, and upon administration, the pharmaceuti useful for continued administration of an active drug sub cal compositions, provide an average steady state trough stance over an interval of about 20 to about 28 hours between (such as the theoretical steady state trough) of the active drug individual administrations, and accordingly, in particular substance selected from at least 20%, at least 25%, and at least embodiments, pharmaceutical compositions as described 35 30% of the average steady state C of the active drug Sub herein have the pharmacokinetic profiles described in this stance. In certain such embodiments, upon administration, section. Accordingly, in specific embodiments, upon admin the pharmaceutical compositions, provide an average steady istration, pharmaceutical compositions according to the state trough of the active drug Substance selected from a range present description give rise to a ratio between trough (or Ca of 20% to 80%, a range of 25 to 80%, and a range of 30 to 80% in embodiments wherein the pharmaceutical composition is 40 of the average steady state C of the active drug substance. for continued administration with an interval of 24 hours Again, in Such embodiments, the active drug Substance between individual administrations) and C, which is suf maybe an opioid such as those described herein. In one Such ficiently high. In particular embodiments the pharmaceutical embodiment, the opioid is oxycodone or a pharmaceutically compositions described herein, upon administration to an acceptable salt thereof individual, do not reach the maximal concentration of the 45 In some embodiments, the pharmaceutical compositions active drug Substance too soon. For example, in Such embodi described herein have a length in a range selected from 7.5 to ments, 50% of C is not reached too soon after the C,flex and 15 mm and 7.5 to 10 mm, said compositions comprise an in certain such embodiments, 50% of C is never reached active drug Substance (for example, an analgesic, such as an because the trough/C ratio is >0.5. In yet further embodi opioid, for example morphine, oxycodone or hydrocodone) ments, pharmaceutical compositions as described herein, 50 described herein, and upon administration, the pharmaceuti when administered frequently enough to reach steady state, cal compositions, provide a steady state C of the active drug the trough provided by the pharmaceutical composition is substance selected from at least 20%, at least 25%, at least Sufficiently high to ensure continuous efficacy over the entire 30%, at least 40%, and at least 50% of steady state C of the administration period. active drug Substance. In such embodiments, the active drug An individual is in steady state with regard to a particular 55 Substance maybe an opioid such as those described herein. In active drug Substance when the plasma concentration level one such embodiment, the opioid is morphine. after one dosing is the same within the standard deviation as The average steady state maybe based on measurements in the plasma concentration level after the following dosing. at least 5 different individuals, such as 5 different human Thus, for pharmaceutical compositions for continued admin beings. Similarly, said average steady state trough may be istration with a 24 hour interval between individual adminis 60 based on measurements in at least 5 different individuals, trations, steady state AUCo.2 AUCo-2,+/- the stan Such as 5 different human beings. dard deviation, and Co-24), Co-24, 1+/- the In respect of the pharmaceutical compositions formulated standard deviation, where d is day. AUC refers to the “area for continued administration with a 24 hour interval between under the curve' and is a measurement for the plasma con administrations, then trough will in general be similar too, or centration over the entire dosing interval. 65 even identical to steady state C. In order to determine steady state parameters, pharmaceu In particular embodiments, upon administration of the tical compositions as described herein may be administered pharmaceutical compositions described herein (in particular, US 9,023,394 B2 47 48 such compositions which have a length of 7.5 to 15 mm such administration of the pharmaceutical composition to a steady as, for example, a length of between about 8 to 10 mm), C fia state individual. For example, the 2" point where a concen is preferably not reached too early after C. Thus, in Such tration of 50% of steady state C. is reached may be in a range embodiments, C, is reached no earlier than half way selected from 4 to 48 hours, 6 to 48 hours, 8 to 48 hours, 10 to through a given dosing interval in a steady state individual. 48 hours, 12 to 48 hours, 14 to 48 hours, 4 to 34 hours, 6 to 34 Thus, in particular embodiments, where the pharmaceutical hours, and 8 to 34 hours after last administration of the phar compositions are prepared for continued administration of an maceutical composition to a steady state individual. In some active drug Substance (for example, an analgesic, such as an embodiments, the 2" point where the plasma concentration opioid, including for example, morphine, oxycodone or reaches 50% of steady state C is not reached within the hydrocodone) over an interval of about 20 to 28 hours, such as 10 interval between administrations, and where such composi a 24 hour interval, between administrations, C, may be tions are administrated continually, the 2" point where the reached at a time selected from no earlier than 10 hours after, plasma concentration reaches 50% of steady state C is not no earlier than 12 hours after, no earlier than 14 hours after, at reached. In particular embodiments, time to 50% of C is least 16 hours after, at least 18 hours after the last adminis determined based on measurements in least 5 different indi tration to an individual. Such as a human being. In specific 15 viduals. Such as human beings. such embodiments, the time when C is reached is deter For continuous administration of an active drug Substance mined as an average based on measurements in at least 5 over an interval of about 20 to 28 hours, such as a 24 hour different individuals, such as 5 human beings. interval, between administrations, pharmaceutical composi In embodiments of the pharmaceutical compositions tions as described herein comprising an active drug Substance described herein, the pharmaceutical compositions, after (for example, an analgesic, such as an opioid, including, for administration, provide a plasma concentration of the active example morphine, oxycodone or hydrocodone), may be for drug Substance that reaches 50% of steady state C twice mulated Such that, after administration to an individual, the after each administration. Once at the time when plasma 1 point where the plasma concentration reaches 50% of concentration is rising Soon after administration (referred to steady state C is not reached too fast. Pharmaceutical 1 point), and once when plasma concentration is decreasing 25 compositions described herein, in particular such composi after the peak concentration has been reached (referred to as tions which have a length selected from a range of 7.5 to 15 2"point). mm and a range of 8 to 10 mm are Suited to achieving such a For continued administration of an active drug Substance pharmacological profile. In certain such embodiments, the 1 over period of time of about 20 to 28 hours, such as a 24 hour point where a concentration of 50% of steady State C is interval, in certain embodiments, the pharmaceutical compo 30 reached is selected from no earlier than 30 min. and no earlier sitions described herein provide a pharmacological profile of than 45 min. In some such embodiments, the 1 point where the active drug substance (for example, an analgesic, such as a concentration of 50% of steady state C is reached occurs an opioid, including, for example, morphine, oxycodone or in a range selected from 45 to 150 min, 45 to 120 min, and 45 hydrocodone), wherein the 2" point where the plasma con to 90 min. after last administration of the pharmaceutical centration reaches 50% of steady state C is not be reached 35 composition to a steady state individual. For example, in too fast or even not at all. In certain Such embodiments, the certain such embodiments, the 1 point where a concentration pharmaceutical composition described herein is a composi of 50% of steady state C is reached occurs in a range tion which exhibits a length selected from a range of 7.5 to 15 selected from 0.25 to 2 hours and 0.5 to 2 hours after last mm and a range of 8 to 15 mm. Additionally, fast onset of administration of the pharmaceutical composition to a steady action for the active drug Substance may be an advantage. 40 state individual. In particular embodiments, the time to 50% Therefore, in particular embodiments, the pharmaceutical of C is determined based on measurements in least 5 compositions described herein are formulated such that, after different individuals, such as human beings. administration to an individual, the pharmaceutical compo In specific embodiments, pharmaceutical compositions as sition provides a pharmacological profile of the active drug described herein are formulated to provide a Tofan active substance with a short time to the 1 point where the plasma 45 drug Substance (for example, an analgesic, such as an opioid, concentration reaches 50% of steady state C. Depending including, for example, morphine, oxycodone or hydroc on the active drug substance to be delivered and the desired odone) selected from a range of 3 to 10hours, 4 to 7 hours, and pharmacological profile, after the initial administration of the 4 to 6 hours after last administration to a steady state indi pharmaceutical composition and during a period of continu vidual. In specific embodiments, T is based on an average ous administration of the pharmaceutical composition, 50% 50 of measurements in at least 5 different individuals, preferably of steady state C may not be reached a second time until 5 human beings. administration of the pharmaceutical composition is termi In some embodiments, the pharmaceutical compositions nated. In Such a situation, if desired, another marker, such as, described herein include 30 mg of an active drug substance for example, 75% of steady state C may be chosen to (such as an analgesic, for example, an opioid such as mor define the period for the passing the first and second time. 55 phine) and exhibit a length of in a range selected from 7.5 to Pharmaceutical compositions as described herein are able 15 mm and 8 to 10 mm, and the pharmaceutical composition to both provide a profile with a high minimum plasma con is formulated to provide a steady state AUCo., of the active centration (C) and alongtime between the first and second drug substance selected from at least 200 nmolh/L, at least time of passing a fraction of C (e.g., 50% or 75% C) and 300 nmolh/L, and at least 350 nmolh/L. In certain such as compared to other controlled release formulations. In par 60 embodiments, the steady state AUCo., of the active drug ticular embodiments, the pharmaceutical compositions substance is selected from a range of 200 to 1000 nmolh/L, described herein provide a pharmacological profile of the a range of 300 to 1000 nmolh/L, a range of 300 to 500 active drug substance, wherein the 2" point where a concen nmolh/L, and a range of 300 to 400 nmolh/L. tration of 50% of steady state C is reached is selected from In some embodiments, the pharmaceutical compositions no earlier than 4 hours, no earlier than 6 hours, no earlier than 65 described herein include 100 mg of an active drug substance 8 hours, no earlier than 10 hours, no earlier than 12 hours, no (such as an analgesic, for example, an opioid such as mor earlier than 14 hours, and no earlier than 15 hours after last phine) and exhibit a length of in a range selected from 7.5 to US 9,023,394 B2 49 50 15 mm and 8 to 10 mm, and the pharmaceutical composition pharmacokinetic profile may be different from those pro is formulated to provide a steady state AUC of the active vided by pharmaceutical compositions formulated for longer drug substance selected from at least 400 nmolh/L, at least dosing intervals. 600 nmolh/L, at least 800 nmolh/L, at least 1000 nmolh/ Thus, for Such formulations, upon administration the aver L., at least 1200 nmolh/L and at least 1400 nmolh/L. In age steady state trough (such as the theoretical steady state certain Such embodiments, the steady state AUCo., of the trough) of the active drug Substance may be in a range active drug substance is selected from a range of 1000 to 3000 selected from a range of 5 to 40%, a range of 5 to 30%, a range nmolh/L, a range of 1000 to 2000 nmolh/L, a range of 1200 of 10 to 30%, a range of 10 to 20%, a range of 14 to 27%, and to 2000 nmolh/L, a range of 1200 to 1600 nmolh/L, and a a range of 8 to 20% of average steady state C of the active 10 drug Substance. In certain such embodiments, the pharmaceu range of 1400 to 1600 nmolh/L. tical compositions may be formulated with a length selected In some embodiments, the pharmaceutical compositions from a range of 4 to 8 mm, a range of 5.5 to 8 mm, and a range described herein include 20 mg of an active drug Substance of 6 to 7.5 mm, with said compositions comprising an active (such as an analgesic, for example, an opioid such as hydro drug Substance (for example, an analgesic, such as an opioid, codone) and exhibit a length of in a range selected from 7.5 to 15 including, for example, morphine, oxycodone or hydroc 15 mm and 8 to 10 mm, and the pharmaceutical composition odone) as described herein. is formulated to provide an AUCo., of the active drug Sub In specific embodiments, of pharmaceutical compositions stance selected from at least 800,000 pmolh/L, at least 900, formulated for continued administration of an active drug 000 pmolh/L, and at least 940,000 pmolh/L. In certain such substance over an interval of about 7 to 20 hours, such as a 12 embodiments, the AUCo., of the active drug Substance is interval, between individual administrations, the pharmaceu selected from a range of 800,000 to 1,200,000 pmolh/L, a tical compositions may be formulated to provide a MRT in a range of 900,000 to 1,200,000 pmolh/L, and a range of range selected from a range of 8 to 15 hours, a range of 10 to 940,000 to 1,100,000 pmol 'h/L. 15 hours, and a range of 11 to 14.5 hours. In certain Such In some embodiments, the pharmaceutical compositions embodiments, the pharmaceutical compositions may be for described herein include 40 mg of an active drug Substance 25 mulated with a length selected from a range of 4 to 8 mm, a (such as an analgesic, for example, an opioid Such as oxyc range of 5.5 to 8 mm, and a range of 6 to 7.5 mm, with said odone) and exhibit a length of in a range selected from 7.5 to compositions comprising an active drug Substance (for 15 mm and 8 to 10 mm, and the pharmaceutical composition example, an analgesic, such as an opioid, including, for is formulated to provide an AUCoast, of the active drug Sub example morphine, oxycodone or hydrocodone) as described stance selected from at least 400 nmolh/L, at least 450 30 herein. nmolh/L, and at least500 nmolh/L. In certain such embodi In specific embodiments of pharmaceutical compositions ments, the AUCoast of the active drug substance is selected formulated for delivery of an active drug substance over an from a range of 400 to 1,000 nmolh/L, a range of 450 to 1000 interval of about 7 to 20 hours, such as a 12 hour interval, nmolh/L, a range of 500 to 1000 nmolh/L, and a range of between administrations, the pharmaceutical compositions 500 to 600 nmolh/L. 35 may comprise an active drug Substance (for example, an Preferably, AUCo., and AUCoast, are determined as an analgesic, such as an opioid, including, for example mor average based on measurements in at least 5 different indi phine, oxycodone or hydrocodone) as described herein, and viduals, for example 5 human beings. beformulated such that, after administration to an individual In particular embodiments, the MRT (mean residence in need thereof, the active drug substance is delivered from time) of the pharmaceutical compositions described herein is 40 the pharmaceutical composition such that the 2" point where Sufficiently long. Thus, in certain embodiments, the pharma the plasma concentration reaches 50% of steady state C, ceutical compositions described herein are formulated for occurs in the range of 4 to 6 hours. In certain such embodi delivery of an active drug Substance (such as an analgesic, ments, the pharmaceutical composition is formulated Such including, for example, an opioid such as morphine, oxyc the length of the pharmaceutical compositions are selected odone or hydrocodone) over an interval of about 20 to 28 45 from a range 4 to 8 mm, a range of 5.5 to 8 mm, and a range hours, such as a 24 hour interval, and to provide an MRT of 6 to 7.5 mm. selected from at least 11 hours, at least 12 hours, at least 13 In particular embodiments of the pharmaceutical compo hours, at least 14 hours, and at least 15 hours. In particular sitions described herein, the Protraction index lies as closely such embodiments, the MRT are selected from a range of 11 to 1 as possible. In such embodiments, the plasma concentra to 30 hours, 12 to 30 hours, 13 to 30 hours, 14 to 30 hours, and 50 tion is substantially constant throughout the 24 hour dosing 15 to 30 hours. interval, i.e., throughout the period between two consecutive The controlled release formulations of active drug sub administrations. Hence, in specific embodiments of the phar stances described herein can be formulated to release the maceutical compositions described herein, the pharmaceuti active drug Substance in a manner that the desired clinical cal compositions are formulated to provide a Protraction efficacy is achieved. For example, where the active drug sub 55 index selected from at least 0.2, at least 0.25, at least 0.30, at stance is an analgesic for the treatment of pain, the pharma least 0.35, at least 0.40, at least 0.45, at least 0.50, at least 0.55, ceutical compositions described herein can be formulated to at least 0.60, at least 0.70, and at least 0.80. provide continued release of the active drug Substance in a Drug Abuse manner that pain is relievedorameliorated in the individual to Pharmaceutical compositions as described herein can be whom the pharmaceutical composition is administered con 60 formulated to provide a reduced risk for drug abuse and/or tinuously throughout the treatment period. alcohol induced dose dumping. For pharmaceutical compositions prepared for continued In particular embodiments, the pharmaceutical composi administration of an active drug Substance over an interval of tions described herein may be formulated to mitigate or pre about 5 to 20 hours, such as a 12 hour interval oran interval in vent alcohol induced dose dumping. In certain such embodi a range selected from a of about 7 to 20 hours, a range of about 65 ments, the pharmaceutical compositions are formulated Such 6 to 18 hours, a range of about 10 to 20 hours, a range of about that the ratio (R50) between tso w/w (40% w/w ethanol in 10 to 18 hours, and a range of about 10 to 16 hours, the medium 1) and tsoo, W/w (medium 1) is 1 or more. tsoo, W/w US 9,023,394 B2 51 52 (medium 1) denotes the time it takes to release 50% w/w of Substance faster than in a dissolution medium which may be the active drug Substance from the pharmaceutical composi either ethanol or phosphate buffer pH 6.8 tion in an in vitro dissolution test according to USP30, NF 25, In the Injection test, the composition is dissolved in 2 ml (711), Apparatus 2, paddle employing water optionally buff water possibly after extensive heating. The preparation is put ered to a specific pH as dissolution medium (medium 1), and into a syringe and the time of passage through a fitted 0.5 mm to w/w (40% w/w ethanol in medium 1) denotes the time it needle is measured upon a weight applied to the Syringe of 3 takes to release 50% w/w of the active drug substance from kg. In specific embodiments, the pharmaceutical composi the pharmaceutical composition in an in vitro dissolution test tions described herein are formulated such that the time of according to USP 30, NF 25, (711), Apparatus 2, paddle passage of the pharmaceutical compositions Subjected to the employing 40% w/w ethanol in medium 1 as dissolution 10 Injection Test is at least 10 sec. Such as at least 15 sec., or at medium. least 20 sec. In a specific embodiment, the ratio R50 is at the most 5, Pharmaceutical compositions described herein are formu such as at the most 4, at the most 3, or at the most 2. Notably, lated to resist abuse by crushing, melting, extraction, disso in specific such embodiments, the ratio R50 provided by the lution, or similar techniques. Furthermore, the pharmaceuti pharmaceutical compositions described herein is from 1 to 15 cal compositions described herein can be formulated to 1.5 such as, for example, from 1 to 1.4, from 1 to 1.3, from 1 exhibit decreased (or essentially the same) release rate in to 1.2, from 1 to 1.1, from 1 to 1.05, about 1, from 1 to 0.95 or alcohol containing media as compared to a purely aqueous from 1 to 0.9. media. The release rate from the pharmaceutical composition The same may also apply for ratios determined, for will depend on several parameters, including, but not limited example, when 25%, 30%, 40%, 60%, 70%, 80%, 90% and/ to: Solubility of the polyglycol, active drug Substance and any or 95% w/w has been released, the conditions being as excipients included in the composition; the wetability of the described above. composition; the diffusion of water into the composition; the The likelihood of a composition being Subject to drug enthalpy of melting and enthalpy of solubilization; and the abuse may for example be tested by different tests: disentanglement rate of the polyglycol during dissolution. 1. Crushing test 25 Controlled release dosage forms are used to extend the release 2. Melting test from the dosage form for an extended period of time. In the 3. Extraction/dissolving test present context the term “controlled release' is used to des 4. Injection test ignate a release a desired rate during a predetermined release In the crushing test, the composition is Subjected to crush period. ing using a hammer or an apparatus designed to measure the 30 All patent and non-patent references cited in the applica hardness of an oral dosage form. A Suitable apparatus is tion are hereby incorporated by reference in their entirety. specified in Ph. Eur. If the composition disintegrates into particles, then it may be possible to dissolve or Suspend these EXAMPLES particles and use them for abuse purposes. Moreover, if it is possible to disintegrate (crush) the composition, then it is 35 The invention is further illustrated in the following non possible to use the powder for Snorting or Sniffing and in this limiting examples. way abuse the composition. However, if it is not possible to crush the composition in this test, then there will be no par Example 1 ticles to use for Such abuse purposes. In particular embodi ments, the pharmaceutical compositions described herein 40 A Single-center, Single Dose, Randomised, Open Label; cannot be crushed into particles by the apparatus specified in Exploratory, 5-way Cross-over Study Evaluating the Pharma Ph. Eur. cokinetic Profile of Various Egalet(R) Hydrocodone Test For In the melting test, the composition is subjected to heating, mulations in Healthy Volunteers Under Fasting Conditions for example, on a spoon or by exposure to microwave induced This study is also referred to as HC-EG-001 herein. heating. If the composition is suitable for susceptible to 45 Design abuse, when Subject to such a test, the composition will The study was a single centre, open-label, single-dose, become so liquid that it is possible to inject it, without being randomised, 4-way crossover, comparative Phase I study, in too hot. However, a composition that is not susceptible to which the pharmacokinetic profile of four different Egalet(R) abuse, when subject to a standard melting test, will not hydrocodone test-formulations was evaluated and compared become a liquid Suitable for injection. Accordingly, in spe 50 to a marketed, reference listed drug (NORCO.R. 10/325). Two cific embodiments, compositions as described herein may be (2) different chemical formulations (with medium and a high formulated such that they do not become so liquid that it is drug load respectively) and three (3) different geometries (6.0 possible to inject them upon Subjecting the compositions mm, 7.5 mm, and 9.0 mm) were developed. For the medium heating in a standard melt test. load formulation, all three geometries were available, In the extraction test, the ease with which it is possible to 55 whereas only the 9 mm was available in the high load formu extract the active drug Substance from the composition by lation. means of normally available organic Solvents is evaluated. If Hydromorphone contributes to the total analgesic effect it is possible to dissolve the composition or extract the active and norhydrocodone is an abundant metabolite. Therefore, drug Substance from the composition using Such organic Sol for the purposes of this study, hydrocodone, hydromorphone vents, then Such a composition is susceptible to abuse. Con 60 and norhydrocodone were measured in plasma samples. versely, if it is not possible to dissolve or extract significant Investigational Products quantities of the active drug Substance from the composition Treatment A: 1x20 mg Egalet(R) hydrocodone PR tablet of using such solvents, then the composition may not be suscep Formulation A, 6.0 mm. tible to misuse. Thus, in particular embodiments, the phar Treatment B: 1x20 mg Egalet(R) hydrocodone PR tablet of maceutical compositions described herein may beformulated 65 Formulation A, 7.5 mm. Such that it is not possible to dissolve the pharmaceutical Treatment C: 1x20 mg Egalet(R) hydrocodone PR tablet of compositions or extract significant amounts of active drug Formulation A, 9.0 mm. US 9,023,394 B2 53 54 Treatment D: 1X20 mg Egalet(R) hydrocodone PR tablet of Primary bioequivalence analysis of hydrocodone where Ct Formulation B, 9.0 mm. was the last sample above LOQ. Treatment E (Reference): 1x NORCO.R. 10/325 IR tablet 3) C. maximum observed concentration: were derived (containing 10 mg hydrocodone bitartrate and 325 mg from the samples 0-42 h after drug administration. Actual acetaminophen). sampling time points were used for T. Treatments A through D are pharmaceutical compositions 4) Residual area: calculated as 100*(1-AUCo/AUCo.). prepared according to the present description. The composi 5) T. time of observed C. were derived from the tions of the products are shown herein below in Example 3, samples 0-42 h after drug administration. Actual sampling Tables 16 and 17. time points were used for T. Methodology 10 6) Tel: elimination half-life was found by Ln(2)/K. The 28 healthy, adult subjects enrolled in this study were 7) K: elimination rate constant: was the slope of the terminal members of the community at large. Subjects were judged part of the log-concentration-time-curve and was found eligible for participation in the study when assessed against using log-linear regression. The final three plasma concen the inclusion and exclusion criteria. trations above LOO were included in the calculation as a 15 minimum. However, the log-linear plots of plasma concen In each period, drug administration was performed on the tration were inspected and a different selection of data morning of Day 1, after Subjects had undergone a Supervised points could have been chosen to ensure that the time overnight fast of at least 10 hours. Subjects, seated in upright period represented the terminal elimination phase. Actual position, were administered a single oral dose of either Ega time values were used. let(R) hydrocodone 20 mg test formulations or NORCOR) 8) MRT. Mean residence time; was calculated as 10/325 with approximately 240 mL of water. Subjects were dosed as specified in the protocol, and sub MRTo-AUMCoAAUCo. where sequently fasted for a period of at least 4 hours. Subjects were instructed to swallow the study medication whole. There were washout periods of 6-7 days or more between doses. 25 and where AUMC was the area under the first moment Sample Collection curve from time 0 until the last valid measurement at the time In each period, all blood samples were drawn into blood point t. Ct was the last valid plasma concentration found at collection tubes (1x4 mL) containing EDTAK2; prior to drug this time point, t. administration and 0.333, 0.667, 1.00, 1.33, 1.67, 2.00, 2.50, 9)AUCo. and AUCo. were calculated by utilisation of the 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 15.0, 30 linear trapezoidal method in the same way as for AUCo. 18.0, 21.0, 24.0, 27.0, 30.0, 36.0, and 42.0 hours post-dose. 11) Proportion AUCo. was calculated as When deemed appropriate by the clinical staff, and as agreed upon by the Subject, a dead-Volume intravenous catheter was Proportion AUCo-1-100 AUCo. (AUCo. used for blood collection to avoid multiple skin punctures. 12) Protraction index (AUCoa/24 h)/C was calculated Otherwise, blood samples were collected by direct venipunc 35 for each individual with regard to the hydrocodone con ture. centration profile Safety Pharmacokinetic Methods The safety assessments were including vital signs, ECGs, Numerical data was presented in Summary tables by num biochemistry, hematology, urine analysis, urine drug screen, ber of Subjects, arithmetic mean (geometric mean and CV pregnancy tests and adverse experience recording. They were 40 where applicable), median, standard deviation, minimum and conducted according to standard medical practices and are maximum. Categorical data is presented by number and per generally accepted as reliable, accurate, and relevant. The cent of subjects as well as number events (where applicable). study data were analysed using standard methods widely All calculations of endpoints, analyses and presentation of accepted by medical and regulatory agencies. endpoints were carried out in SAS version 9.1 (Statistical Pharmacokinetic Parameters 45 Analysis System) or later versions. Analysis datasets were The following pharmacokinetic parameters were calcu derived from the study data and was adhere to the CDISC lated by standard non-compartmental methods for hydroc ADaM standard (Clinical Data Interchange Standard Consor odone plasma concentrations: tium Analysis Data Model). 1) AUC(0-t): area under the concentration-time curve from For the hydrocodone AUCo. 42. AUCo. and C, primary time Zero to the last non-Zero concentration: The area under 50 PK parameters, the ratio between test treatments A, B, C and the concentration-time-curve from time Oh until the last D compared to treatment E (reference) were, after log trans concentration sample at time 42 h, AUCo., were calculated formation, estimated in a mixed linear model as by the linear trapezoidal method, using the actual sampling time points. If the last blood sample was taken less than 42 Log(Endpoint)=Treatment+Period+Subject+random hours after drug administration, the 42 h values were 55 error, extrapolated using the terminal elimination rate constant, Where treatment (A, B, C, D or E) and period were fixed Kelas described below. If the last sample was taken after 42 effects and subject was a random effect. hours, a 42 h value was estimated by interpolation. Inter The estimation included all valid PK data from all treat mediate missing values remained missing (equivalent to ments for each comparison. Treatment sequence was interpolating between neighbouring points when calculat 60 included as a fixed effect in the above model. ing AUC). Intermediate values below the limit of quantifi The ratios of means (A/E, B/E, C/E and D/E) were calcu cation (LOO) were assigned a value of LOO/2, while trail lated with 90% geometric confidence intervals based on least ing values below LOO were assigned a value of Zero. squares means. The treatment difference and corresponding 2) AUCo. area under the concentration-time curve from confidence interval were back-transformed, thus yielding time zero to infinity (extrapolated): was determined for 65 ratio estimates. Hence, the CI was evaluated against the range profiles that did not return to Zero within 42 hours. (0.80; 1.25). AUCo. was calculated as the sum of AUCo., and Ct Other endpoints were tabulated. US 9,023,394 B2 55 56 Pharmacokinetic Results TABLE 2 A total of 28 subjects were enrolled in the study. Twenty eight (28) subjects received at least one dose of the study Hydromorphone pharmacokinetic parameters (dose-normalised medication and comprised the safety population. The phar macokinetic analyses included 22 subjects who completed at 5 to 10 mg) for each treatment (N = 22) least 2 periods, 21 Subjects who completed at least 4 periods, and 19 subjects who completed the study. AUCo. 42 AUCo., Cmax The mean dose-normalized AUCo., and AUCo-values for """ (pmol himL) (pmol himL) (pmol/mL) all Egalet(R) test PR formulations were similar to those obtained for the reference IR formulation (NORCO.R. 10 Formulation A; 6 mm (A) 9070.15 9994.89 465.64 10/325) as evidenced by the ratios and 90% confidence inter- Formulation A; 7.5 mm (B) 831816 92.55.32 369.78 vals contained within the interval limits of 80%-125%. As Formulation A; 9 mm (C) 8405.98 96.39.06 313.23 expected, the mean C. values for all test PR formulations Formulation B; 9 mm (D) 8534.74 10443.43 306.84 were lower than those observed for the reference IR formu- NORCO (R) 10/325 (E) 8S90.99 9.SSO.34 989.60 lation (NORCO.R. 10/325). The ratios of the least-squares 15 means (Test/Reference) were 48%, 40%, 30% and 28% for *For this parameter, N = 20 for Treatments C and D. formulations A1, A2, A3 and B1, respectively.

TABLE 1. TABLE 3 Hydrocodone pharmacokinetic parameters (dose-normalised to 10 mg) 2O Norhydrocodone pharmacokinetic parameters (dose-normalised to for each treatment (N = 22 10 mg) for each treatment (N = 22 AUCo. 42 AUCo.; Cmax AUCo. 42 AUCo. if Cmax Treatment (pmol himL) (pmol himL) (pmol/mL) Treatment (pmol himL) (pmol himL) (pmol/mL) Formulation A; 6 mm (A) 526858.92 S33766.04 38434.97 25 Formulation A; 6 mm (A) 182950.37 1883S1.73 10492.78 Formulation A; 7.5 mm (B) S41913.82 SS4169.22 31949.23 Formulation A; 7.5 mm (B) 178872.71 188108.45 8431.64 Formulation A; 9 mm (C) 479527.18 499662.11 24O1817 Formulation A; 9 mm (C) 159263.OO 173834.25 6938.85 Formulation B; 9 mm (D) SO6327.16 528655.35 23021.18 Formulation B; 9 mm (D) 157005.92 173530.75 S988.92 NORCO (R) 10/325 (E) S34903.70 S41562.13 81660.68 NORCO (R) 10/325 (E) 191267.71 196338.68 17984.46

TABLE 4

Summary of hydrocodone pharmacokinetic parameters for each treatment (N = 22)

Formulation A Formulation A Formulation A Formulation B 6 mm (A) 7.5 mm (B) 9 mm (C) 9 mm (D) NORCO (R) (N = 20) (N = 20) (N = 20) (N = 20) 10/325 (E) Mean Mean Mean Mean (N = 21) Parameters (min-max) (min-max) (min-max) (min-max) Mean

AUCo. (pmol 1053717.85 1083,827.64 959054.36 101.2654.33 S34903.70 h/mL) (566723-15O1558) (573855-1601524) (513753-1412443) (511294-14885.50) (263O32-854269) AUC (pmol 1067532.07 1108338.44 999324.21 1057310.70 S41562.13 h/mL) (570971-1525746) 579026-1640043) (518.525-1455476) (518118-1587096) (268171-867127) Residual (%) 1.25 2.10 3.73 4.13 1.23 808 (0.64-2.48) (0.81-4.38) (0.76-11.89) (1.32-9.53) (0.59-2.62) Cmax (pmol/mL) 76869.94 63898.46 48O36.34 46042.36 81660.68 (52083-105730) (44804-93280) (31808-88033) (28407-69417) (44714-130655) Tmax (h) 6.25 5.38 5.25 4.52 1.08 (4.5-10.0) (2.5-15) (3.5-10.0) (3.00-7.00) (0.67-2.00) Tmax" (h) 4.75 4...SO 4.75 4SO 1.00 Kei (h) O.1204 O.11.78 O. 1196 O. 1174 O.1176 (0.0839-0.1611) (0.0870-0.1684) (0.0568-0.1794) (0.0733-0.1737) (0.0695-0.1569) T12 el (h) S.91 6.07 6.11 6.11 6.16 (4.30-8.26) (4.11-7.97) (3.86-12.20) (3.99-9.46) (4.42-9.97) MRT (h) 11.73 1423 17.09 18.12 7.69 (9.49-13.99) (10.63-16.75) (10.18-21.61) (15.72-20.89) (5.73-10.56)

Median. US 9,023,394 B2 57 58 The protraction index was determined, and the data below Discussion in Table 5 are derived from the hydrocodone concentration The median T for the four EgaletR) formulations was profile obtained in the individuals that participated in this almost identical and between 4.50 hours (treatment A & C) study. and 4.75 (treatment B & D), whereas the median T for Norco 10/325 was 1.00 hour. NORCO.R. 10/325, when dosed in half nominal dosage of TABLE 5 the Egalet(R) formulations gave rise to a C of 81661 pmol/ Protraction index mL, slightly higher than the C (76870 pmol/mL) obtained for treatment A, the Egalet(R) formulation resulting in the Formula highest C. When dose-normalized and tested for equiva Formulation A Formulation A Formulation A tion B 10 lence, the ratios of least-square means were below 50% for all (6 mm) (7.5 mm) (9mm) (9mm) Norco Egalet(R) formulations, which indicates the prolonged and (AUCo 24, 24 h).C. slower release from the Egalet(R) formulations. Both treatment A and treatment B might be relevant can O43 O.65 O.70 O.63 O.31 didates to consider for a twice daily dosage regimen. For O.S6 O.63 0.67 O.64 O.30 15 O.S1 O.S3 O.63 0.72 O.24 treatment C and D, which both have the same geometry, but O.S2 O.S8 O.60 O.69 O.26 different chemical compositions, the mean concentration O.S8 O.47 O.64 0.67 O.24 time-curves display an almost identically pattern. These two O.39 O.S4 O.49 O.S8 O.25 formulations have prolonged in-vivo profiles, with fairly con O42 O46 O.S6 O.61 O.24 stant hydrocodone concentrations until the 24 hours post O43 0.72 O.48 0.55 O.25 O.66 O.S1 O.80 O.68 O.24 dose time-point, after which elimination occurs. Both release O.S1 O.62 O.66 0.73 O41 profiles provide once-daily dosing characteristics. Further, O48 O.S6 O.74 O.61 O.20 treatment D, for example, illustrates the viability of develop O49 O.74 O.76 O.69 O.18 ing relatively higher dose-strength compositions, which can O.63 O.67 0.72 0.79 0.37 be relevant for opioid tolerant patients. O.67 O.63 O.38 0.57 O.32 25 When dose-normalized, all Egalet(R) formulations were O.S9 O.63 0.67 0.79 0.27 found to provide the same total hydrocodone exposure as O49 O.S3 O.74 0.72 O.29 Norco 10/325. CI's for point-estimates for Egalet(R) treat O.47 O.68 O.61 O.62 O.25 OSO O.6O O.62 O.S1 O.31 ments A and B did include 100%; CI's for treatment A rang O.S2 O.67 O.63 O.65 O.26 ing from approximately 95%-103% and for Treatment B 0.73 O.68 0.79 O.22 30 ranging between 97-107%. Point-estimates for treatment C O.S6 O.61 O.23 and D were below 100%, lowest for formulation C, but point O.70 O.81 estimates and corresponding 90% confidence limits were all Mean within 80-125% acceptance limits, and thus considered equivalent. AUC equivalence was also found for metabolites. O.S2 O.61 O.64 0.67 0.27 Steady State Pharmacokinetics Simulation Min 35 The individual patient data from study HC-EG-001 were simulated to Steady state to derive the steady state parameters O.39 O46 O.38 O.S1 O.18 of the Egalet(R) formulations tested and to assess the indi Max vidual ranges for C/C Supporting the use of Egalet(R) O.67 O.74 O.80 O.81 O41 Hydrocodone for administration with 24 hours interval. 40 Method for SS Simulation The individual steady state data in the time interval Oh, 24 FIGS. 1 to 3 show the mean plasma concentration versus h were estimated as a sum of two components a) the sample time profiles for hydrocodone, hydromorphone and norhy values in the Oh, 24h interval and b) estimated tail values in the interval 24 h, infinity, for example, the estimated value drocodone after single dose administration by dose group at 1 hour on day 2, 3, 4 etc. This corresponds to the Superim (0-42 h). 45 position principle. The tail was assumed to follow the stan Safety Results dard one-compartment elimination (i.e. exponential func tion), and was estimated based on sample data from 24-42 No severe, significant, or serious adverse events were hours for Hydrocodone and derivatives. reported during the study. The frequency of adverse event The estimated tails after 42 h were less than 20% of total observations did not appear to be related to treatment. Over 50 area and were included in the modelling. all, adverse events were mild or moderate in intensity and For Hydrocodone the reference dose was 10 mg while were, except for a few, expected opioid effects. No safety test-doses were 20 mg. No dose normalisation was per concerns with respect to the clinical laboratory tests, vital formed. signs, and ECGs were raised. Results TABLE 6 Summary of Steady State Parameters Peak Trough Trough Peak Tmax (pmol/mL) (pmol/mL) Ratio (Hours)

Treatment N 2O 2O 2O 2O A 6.0 mm Mean 82873 12136 O.14 6.25 Median 82296 11931 O.14 4.75 Range 54340-11 1354 4620-25139 O.O6-0.27 4.50-10.00 A 7.5 mm N 2O 2O 2O 2O Mean 7.5908 2O241 O.26 5.38 US 9,023,394 B2 59 60 TABLE 6-continued Summary of Steady State Parameters

Peak Trough Trough Peak ex (pmol/mL) (pmol/mL) Ratio (Hours) Median 74781 19423 0.27 4...SO Range S1907-107306 S954-33S12 O.11-0.37 2.50-1S.OO A 9.0 mm N 22 22 22 22 Mean 67119 26909 O.40 5.25 Median 657.26 27115 O.42 4.75 Range 43067-109224 4626-41216 O.08-0.52 3.50-10.00 B 9.0 mm N 22 22 22 22 Mean 68359 291.21 O.42 4.52 Median 66746 26434 O.42 4...SO Range 38985-107SO7 12482-48370 O.30-0.56 3.00-7.00 Reference N 2O 2O 2O 2O Mean 86525 3368 O.04 1.OS Median 83719 2855 O.O3 1.OO Range S4982-137908 1324-7698 O.O2-0.08 O.67-2.OO

FIG. 4 shows an estimated steady state hydrocodone curve TABLE 7-continued The results of this study further illustrate that the formula tion and configuration of pharmaceutical compositions Treatments according to the present description can be adjusted to Treatment regimens Co-administration achieve desired delivery characteristics and pharmacokinetic 25 Treatment C (test 3, 9.0 mm): 1 x 40 mg Naltrexone 1 x 50 mg profiles. For example, in this study, a relatively short Egalet(R) Egalet (R) oxycodone 12 and 1 hour prior to dosing formulation with a relatively wide release area (A1, 6 mm of treatment regimen A-D length) provides a realtive fast release rate and a C and Treatment D (reference): 1 x 40 mg Naltrexone 1 x 50 mg OxyContin (R) (containing oxycodone) 12 and 1 hour prior to dosing AUC equivalent to the immediate release comparator product of treatment regimen A-D Norco(R). The profile patterns are similar for the metabolites. 30 Alonger geometry with a smaller area exposed for release at the open ends of the Egalet(R) formulation provides a lower The composition of the formulations is given in Example3, C and release over a longer period providing a more sus Table 12 herein below. tained plasma profile. Methodology 35 For each period, subjects were confined to the clinical Example 2 research facility from at least 14 hours prior to drug admin istration and were discharged from the clinic at least 48 hours A Randomized, Comparative, Open-label, Crossover, after study drug administration. The treatment phases were Phase I Study Evaluating Single Dose Pharmacokinetic Pro separated by washout periods of 7 days. files of Various Egalet(R) Oxycodone 40 mg Test Formulations 40 In each period, Subjects were administered a single oral Versus OxyContin R in Healthy Volunteers. Using Naltrexone dose of one of the three Egalet(R) oxycodone 40 mg or Oxy Blockade Under Fasting Conditions Contin R (as one 40 mg controlled release tablet), in accor The study is also referred to as OC-EG-001 herein. dance with the Subjects randomization sequence under fast Design ing conditions. 50 mg Naltrexone was co-administered (to The study was a single centre, open-label, single-dose, 45 alleviate or avoid opioid side effects) in opioid-naive sub randomised, 4-way crossover, comparative Phase I study, jects, as presented in Table 7. wherein the PK profiles of single doses of three different Sample Collection geometries (6.0 mm, 7.5 mm and 9.0 mm) of Egalet(R) oxyc In each period, all blood samples were drawn into blood odone 40 mg tablets prepared according to the present collection tubes (1x4 mL) containing potassium EDTA K2: description were evaluated and compared to a marketed, ref 50 prior to drug administration and 0.333, 0.667, 1.00, 1.50, erence listed drug. OxyContin R 40 mg. 2.00, 2.50, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00, 10.0, Primary pharmacokinetic analyses were performed with 12.0, 16.0, 20.0, 24.0, 30.0, 36.0, and 48.0 hours post dose. measurements of oxycodone plasma concentrations and sec When deemed appropriate by the clinical staff, and as ondary analysis of the plasma concentrations of the active agreed upon by the Subject, a dead-Volume intravenous cath metabolites noroxycodone and oxymorphone. 55 eter was used for blood collection to avoid multiple skin punctures; collections were performed via direct Venipunc TABLE 7 ture, otherwise. Pharmacokinetic Parameters Treatments The following PK parameters were calculated and sum 60 marised by standard non-compartmental methods for oxyc Treatment regimens Co-administration odone plasma concentrations, noroxycodone and oxymor Treatment A (test 1, 6.0 mm): 1 x 40 mg Naltrexone 1 x 50 mg phone plasma concentrations respectively. The PK endpoints Egalet (R) oxycodone 12 and 1 hour prior to dosing were calculated individually for each subject and treatment of treatment regimen A-D Treatment B (test 2, 7.5 mm): 1 x 40 mg Naltrexone 1 x 50 mg for the plasma concentrations obtained on Days 1-3 (0-48 h) Egalet (R) oxycodone 12 and 1 hour prior to dosing 65 within each period. of treatment regimen A-D 1) AUCo. area under the concentration-time curve from time Zero to the last non-zero concentration: The area under US 9,023,394 B2 61 62 the concentration-time-curve from time Oh until the last 9)AUCo. and AUCo. were calculated by utilisation of the concentration sample at time 48 h, AUC were calculated linear trapezoidal method in the same way as for AUC. by the linear trapezoidal method, using the actual sampling 11) Proportion AUCo., was calculated as time points. If the last blood sample was taken less than 48 hours after drug administration, the 48 h values were Proportion AUCo-1-100 AUCo. (AUCo. extrapolated using the terminal elimination rate constant, 12) Protraction index (AUCoa/24 h)/C was calculated Kelas described below. If the last sample was taken after 48 for each individual with regard to the hydrocodone con hours, a 48 h value was estimated by interpolation. Inter centration profile mediate missing values remained missing (equivalent to Pharmacokinetic Methods interpolating between neighbouring points when calculat 10 Numerical data was presented in Summary tables by num ing AUC). Intermediate values below the limit of quantifi ber of Subjects, arithmetic mean (geometric mean and CV cation (LOO) were assigned a value of LOO/2, while trail where applicable), median, standard deviation, minimum and ing values below LOO were assigned a value of Zero. maximum. Categorical data is presented by number and per 2) AUCo. area under the concentration-time curve from cent of subjects as well as number events (where applicable). time zero to infinity (extrapolated): was determined for 15 All calculations of endpoints, analyses and presentation of profiles that did not return to Zero within 48 hours. endpoints were carried out in SAS version 9.1 (Statistical AUCo., was calculated as the sum of AUCo., and Ct Analysis System) or later versions. Analysis datasets were Primary bioequivalence analysis of Oxycodone where Ct derived from the study data and was adhere to the CDISC was the last sample above LOO. ADaM standard (Clinical Data Interchange Standard Consor 3) C. maximum observed concentration: were derived tium Analysis Data Model). from the samples 0-48 h after drug administration. Actual For the oxycodone AUCoas, AUCo. and C, primary sampling time points were used for T. PK parameters, the ratio between test treatments A, B, and C 4) Residual area: calculated as 100*(1-AUCo/AUCo.). compared to treatment D (reference) were, after log transfor 5) T. time of observed C. were derived from the mation, estimated in a mixed linear model as samples 0-48 h after drug administration. Actual sampling 25 time points were used for T. Log(Endpoint)=Treatment+Period+Subject+random 6) Tel: elimination half-life was found by Ln(2)/K. error, 7) K: elimination rate constant: was the slope of the terminal Where treatment (A, B, C, or D) and period were fixed part of the log-concentration-time-curve and was found effects and subject was a random effect. using log-linear regression. The final three plasma concen 30 The estimation included all valid PK data from all treat trations above LOQ were included in the calculation as a ments for each comparison. Treatment sequence was minimum. However, the log-linear plots of plasma concen included as a fixed effect in the above model. tration were inspected and a different selection of data The ratios of means (A/D, B/D, and C/D) were calculated points could have been chosen to ensure that the time with 90% geometric confidence intervals based on least period represented the terminal elimination phase. Actual 35 squares means. The treatment difference and corresponding time values were used. confidence interval were back-transformed, thus yielding 8) MRT. Mean residence time; was calculated as ratio estimates. Hence, the CI was evaluated against the range MRTo-AUMCo., AUCo., where (0.80; 1.25). Other endpoints were tabulated. AUMCo., AUMCo.--t"Ct/K+Ct(K)2, 40 Pharmacokinetic Results and where AUMC was the area under the first moment 28 Subjects were screened for this study and upon comple curve from time 0 until the last valid measurement at the time tion of all screening procedures a total of 16 healthy, adult point t. Ct was the last valid plasma concentration found at non-smokers were enrolled in the study, of which 9 com this time point, t. pleted all treatment groups. TABLE 8 Primary Analysis of Oxycodone, Noroxycodone and Oxymorphone Bioeguivalence), Full PK data set:

Test Reference

Test Reference

N Mean in Mean Ratio (%) 90% CI P-value Oxycodone

6.0 mm vs AUCo. 48) 12 S74.7 11 S47.8 104.9 (95.8, 115.0) 0.3790 Reference (nmol * h L) AUCo.it) 12 S7S.O. 11 S49.6 104.6 (95.3, 114.8) 0.4162 nmol * h L) Cmax 12 45.4 11 52.2 87.O (79.0, 95.8) 0.0201 (nmol/L) 7.5 mm vs AUCo. 48) 12 S26.6 11 S47.8 96.1 (87.6, 105.5) 0.4756 Reference (nmol * h L) AUCo.it) 12 S29.1 11 S49.6 96.3 (87.6, 105.8) 0.4992 nmol * h L) Cmax 12 37.4 11 52.2 71.7 (65.0, 79.1) <.0001 (nmol/L) US 9,023,394 B2 63 64 TABLE 8-continued Primary Analysis of Oxycodone, Noroxycodone and Oxymorphone Bioeciuivalence). Full PK data set: Test Reference

Test Reference N Mean in Mean Ratio (%) 90% CI P-value 9.0 mm vs AUCoas 1 S34.9 S47.8 97.7 88.9, 107.3 0.6711 Reference (nmol * h L) AUCoin) 1 542.6 549.6 98.7 89.7, 108.7 O.8222 nmol * h L) Cmax 1 314 52.2 60.1 54.5, 66.4 (nmol/L) Noroxycodone 6.0 mm vs AUCoas 2 606.6 576.3 105.3 (97.8, 113.3) O.2469 Reference (nmol * h L) AUCoin) 2 612.8 S86.5 104.5 (97.3, 112.3) O.3064 nmol * h L) Cmax 2 37.3 38.3 97.4 (90.9, 104.3) 0.5175 (nmol/L) 7.5 mm vs AUCo as 2 SO8.2 576.3 88.2 (81.8, 95.1) O.OO82 Reference (nmol * h L) AUCo. 2 S19.1 S86.5 88.5 (82.3,95.2) O.OO84 nmol * h L) Cmax 2 28.9 38.3 75.6 (70.5, 81.1) <.OOO1 (nmol/L) 9.0 mm vs AUCoas 1 540.1 576.3 93.7 (86.9, 101.1) 0.1575 Reference (nmol * h L) AUCo. 1 S65.9 S86.5 96.5 (89.6, 103.9) O.418S nmolh/L) Cmax 1 38.3 25.6 67.0 (62.4, 71.9) (nmol/L) Oxymorphone 6.0 mm vs AUCoas 2 9.6 11.5 83.6 (69.5, 100.6) O. 1100 Reference (nmol * h L) AUCo. 1 14.9 9 16.4 90.8 (78.0, 105.6) O.2829 nmol * h L) Cmax 2 0.7 O.8 87.5 (76.9,99.5) O.O882 (nmol/L) 7.5 mm vs AUCoas 2 9.2 11.5 80.1 (66.3, 96.7) O.OSS1 Reference (nmol * h L) AUCo. 1 148 9 16.4 90.1 (77.3, 104.9) O.2SO6 nmolh/L) Cmax 2 O6 O.8 75.7 (66.4, 86.3) O.OO12 (nmol/L) 9.0 mm vs AUCoas 1 104 11.5 90.4 (74.7, 109.5) 0.3778 Reference (nmol * h L) AUCo. O 18.7 9 16.4 113.9 (97.5, 133.0) O.1635 nmol * h L) Cmax 1 O.S O.8 70.6 (61.9, 80.6) O.OOO1 (nmol/L)

TABLE 9 TABLE 9-continued 50 Endpoints for Oxycodone Endpoints for Oxycodone

Treatment 6.0 mm 7.5 mm 9.0 mm Reference Treatment 6.0 mm 7.5 mm 9.0 mm Reference AUCo. 48 (nmol hiL): 55 Residual area (Pct.):

Mean S86 537 S62 569 Mean Min, Max 462-880 402-693 384-774 4O3-806 Min, Max O-3 AUCo. (nmol h/L): Tmax (h): 60 Mean 587 S4O 571 571 Mean 4.9 4.4 4.2 2.2 Min, Max 461-882 414-695 387-778 405-811 Min, Max 2.5-10.O 2.0-6.O 1.O-6.O O.7-4.O C (nmol): T1/2) (h):

Mean 46 38 33 S4 65 Mean 4.5 5.2 5.7 5.2 Min, Max 32-59 27-56 23-45 39-79 Min, Max 3.5-5.5 4.1-10.3 3.7-12.5 4.2-6.3 US 9,023,394 B2 65 66 TABLE 9-continued TABLE 10-continued

Endpoints for Oxycodone Protraction index

Treatment 6.0 mm 7.5 mm 9.0 mm Reference 6 mm 7.5 mm 9mm Reference Elimination rate (1/h): Max Mean O16 O.14 O.13 O.14 Min, Max 0.13-0.20 O.O7-0.17 O.O6-0.19 O.11-0.17 MRT (h): 10 FIGS. 5 to 7 show the mean plasma concentration versus Mean 1O.O 11.9 15.6 10.1 time profiles for oxycodone, oxymorphone and noroxyc Min, Max 8.1-11.6 9.2-14.O 13.1-21.7 9.5-10.7 odone after single dose administration by dose group (0-48 h) Proportion AUCO Imax) (Pet.): Safety Results Mean 26 2O 15 (7) 12 No severe, significant, or serious adverse events were Min, Max 11-50 9-30 3-2S 2-24 reported during the study. The most frequently occurring 15 adverse events were expected or procedure-related and were mild or moderate in intensity The protraction index was determined, and the data below Discussion in table 10 are derived from the oxycodone concentration From, the descriptive summaries of AUCoas, and AUCo. profile obtained in the individuals, which participated in this in?) in Table 8 and 9, it was clear that the reference group had study. similar values of AUCo. as and AUCo. compared to the values for the test tablets. C decreased with increasing size TABLE 10 of the tablets. The pattern was repeated for the metabolites noroxycodone and oxymorphone. The elimination rate was Protraction index almost the same for all four treatment groups. Mean MRT 25 increased with increasing size of the tablet, with the reference 6 mm 7.5 mm 9mm Reference group matching the 6.0 mm group. The mean proportion of (AUCo 24, 24 h).C. AUCo., decreased with increasing size of the tablet, as with AUCo. as and C. O.48 O.S6 O.64 O.47 The ratio for C showed a decreasing trend with increas O.48 O.SO OSO O.38 O.48 O.47 0.55 O41 30 ing size of tablets. It was indicated that the 6.0 mm tablet was O.45 O46 O.S3 O.32 closest to the reference tablet, as the 90% confidence intervals O.60 0.58 0.56 0.44 for C were 79.0-95.8 and that the 9.0 mm tablet had the O.S2 O.63 O48 0.37 most sustained profile, with a potential for QD (once daily) O.S9 O.S2 O.68 O.SO dosing. O.S4 O.68 O.S3 O46 Method for SS Simulation O.S1 O.S8 O.63 O.33 35 O.S1 O.S9 O.S1 O.47 The individual steady state data in the time interval Oh, 24 O.S1 O.S6 O.S4 O.49 h were estimated as a sum of two components a) the sample 0.55 O.S3 O.S4 values in the Oh, 24h interval and b) estimated tail values in O.62 the interval 24h, infinity, for example the estimated value at Mean 1 hour on day 2, 3, 4 etc. This corresponds to the Superimpo 40 O.S3 0.55 O.S6 O.42 sition principle. The tail was assumed to follow the standard Min one-compartment elimination (i.e. exponential function), and was estimated based on sample data from 24–48 hours for O.45 O46 O48 O.32 Oxycodone and derivatives. Steady State Results TABLE 11 Summery of Steady State parameters Peak Trough Trough Peak Tmax Analyte Treatment (ngmL) (ngmL) Ratio (Hours)

Oxycodone Reference N 1 1 1 11 Mean 58.78 6.39 O.11 2.20 Median 60.29 5.89 O.11 2.50 Range 41.31-85.57 435-9.81 O.09-014 O.67-40 Test 6.0 mm N 3 3 3 13 Mean 48.04 4.44 O.09 4.89 Median 43.57 3.92 O.08 S.OO Range 33.80-60.94 1.56-7.91 O.04-017 2.50-10.O Test 7.5 mm N 2 2 2 12 Mean 42.22 6.95 O.17 4.38 Median 40.47 6.30 O16 4.75 Range 34.22-58.74 2.62-11.08 O.O7-0.32 2.00-60 Test 9.0 mm N 1 1 1 11 Mean 42.42 3.86 O.33 4.23 Median 39.73 2.30 O.31 4...SO Range 31.38-58.58 9.31-1984 O.25-0.43 1.00-60 US 9,023,394 B2 67 68 FIG. 8 shows an estimated steady state oxycodone curve. The release rate of an active drug Substance can also be From FIG. 8, it is seen that, in this study, the concentration altered by varying matrix composition. For example the dis profile curve of oxycodone flattens with an increase of size of Solution rate of the matrix depends on ingoing components solubility, hydration rate and disentanglement rate among the tablet, and an increase in the tablet size correlated to a other properties. Accordingly, the dissolution rate may be decrease in C. increased by choosing hydrophilic or low molecular weight The individual steady state data Oh, 24 h is estimated as components in the matrix. sum of observed data in the Oh, 24h interval and estimated Table 12 discloses a preparation according to the invention tail values 24h, infinity. Peak and trough were derived from controlling release by tablet length. These preparations were these individual steady state data. The tails were estimated by used in Example 2. standard one-compartment terminal elimination approach. 10 The composition was prepared by two component injec The pattern of increasing Trough/C ratio with increas tion molding. The matrix volume was 125 mm and the ing length for mean oxycodone plasma concentrations is lengths of the different dosage forms were 6 mm, 7.5 mm and similar for the active metabolites mean noroxycodone and 9 mm, respectively. mean oxymorphone plasma. 15 Conclusions TABLE 12 The curve demonstrates that the pharmaceutical composi Quantity tions prepared as described herein facilitate controlled deliv per unit ery of active drug Substances and that the geometry of Such Component Function (mg) % Wiw compositions can be adjusted to achieve desired, prolonged Matrix release of drug Suited to once daily dosing. It is commonly known that enterohepatic cycling causes a Oxycodone hydrochloride Active ingredient 40.O 26.8 Polyethylene oxide 200,000 Carrier 38.4 25.7 multiple peak phenomenon in the concentration-time pro Polyethylene oxide 300,000 Carrier 29.9 2O.O files. Oxycodone does not show enterohepatic cycling. Poloxamer 188 Co-carrier, 14.9 1O.O 25 Plasticizer Example 3 Poloxamer 407 Co-carrier, 20.9 14.O Plasticizer Butylhydroxytoluene Antioxidant, O.O7 O.S Compositions Stabilizer The tablets formulated and used in the Examples are a Eudragit L100-55 Carrier, Stabilizer 4.48 3.0 combination of a matrix polymer system and a water-imper 30 meable, essentially non-erodible shell (coating) partly cover Total, matrix 148.7 1OO.O ing this matrix. The active drug substance is dispersed and/or Shell (coating) dissolved in the matrix. Ethylcellulose Coat material 84.2 87.O The active drug Substance is released substantially by Sur Cetostearyl alcohol Plasticizer 10.1 12.O Titanium dioxide Colorant 0.97 1.O face erosion. The erosion of the matrix occurs when water 35 diffuses into the matrix at a constant rate, leading to polymer hydration, Swelling, disentanglement and dissolution. Total, shell (coating) 96.8 1OO.O A cylindrical shaped shell (coating) with a well defined Total 245.4 surface area in both ends of the tablet leads to constant dis Solution because of a constant release area. Accordingly, a 40 Zero-order release mechanism can be obtained. The shell The release time in an in vitro study (tested in an USP2 (coating) can formulated Such that it is slowly degradable and apparatus at 50 rpm and pH 6.8) is proportional to the length passes Substantially (or entirely) intact through the GI tract of the tablet. The release time is shown in Table 13. and is excreted with feces. For tablets of a given length, extended release over a pre-defined period of time can be TABLE 13 achieved, and as illustrated by the examples provided herein, 45 in certain embodiments, tablets with a length in a range Batch Release time (release) selected from a range of 8 to 10 mm and a range of 9 mm to 6 mm length (batch no. 08-0088-114) 405 min (94%) 9.5 mm can be formulated to provide in vivo efficacy for 24 7.5 mm length (batch no. 08-0089-114) 510 min (88%) hours. 9 mm length (batch no. 08-0090-114) 600 min (88%) Geometry 50 By varying the size of the tablet and the thickness of the The relationship between release time and tablet length is shell (coating), and thereby the matrix weight and size of the shown in FIG. 9. erosion area controlled release properties can by varied. Thus, Table 14 discloses compositions designated formulation A the release area can be adjusted to alter the rate of which drug and B. is released, and the length of the matrix can be adjusted to 55 The compositions were prepared by two component injec alter the duration of the release of drug. It is thus possible, if tion molding. Two different formulations with different com desired, to use the same matrix composition for all strengths that is needed. By varying the length of the tablet, keeping the positions were tested. Both formulations showed the same volume fixed, it is possible to vary dissolution time with a dissolution properties as tested in an USP 2 apparatus at 50 fixed matrix composition. Thus, the duration of the release rpm and pH 6.8 (see FIG. 10). The two formulations were depend on the length of the composition. The rate of release 60 tested in two different tablet shapes: round (formulation A) (mg/h) may depend on the release area. To increase the and elliptical (formulation B). Formulation B was tested in strength of a pharmaceutical composition without changing different sizes, systematically varying Volume and release the duration of the dissolution process, the length is kept area. It was found that the release duration for these formu constant while the area may be increased proportionally with lations did not vary with Volume, area or shape, but appeared the dose. The pharmaceutical compositions disclosed herein, 65 to be dependent on the length. The dose was released propor therefore, enable formulations with different release proper tionally to the release area, Such that each composition ties without changing chemistry of the formulation. released the complete dose (100%) at the same timepoint. US 9,023,394 B2

TABLE 1.4 TABLE 1.5 Amount per tablet (% WW) Function Length Volume Release area Dose Shape Batch no. (mm) (mm) (mm) (mg) Components Form. A Form. B 5 Matrix 1OO 1OO Round O8-O141-066 9 150 16.67 30 Morphine Sulfate 16.O 51.5 Active ingredient Ellipse O8-0140-066 7.5 42.08 S.61 30 pentahydrate Polyethylene 71.4 — Carrier, release ellipse 08-0138-066 7.5 89.94 11.99 60 oxide 200 000 modifier 10 ellipse O8-O137-066 7.5 150.2 2O 100 Polyethylene oxide 300 000 32.0 modifierCarrier, release Ellipse 08-0139-066 7.5 3OO.O2 40 200 Poloxamer 188 13.4 Co-carrier, Plasticizer Mannitol 1O.O 3.0 Release modifier and stabilizer Butylated 0.1 Antioxidant, Stabilizer 15 - Table 16 and 17 shows preparations according to the inven hydroxytoluene tion controlling the release by tablet length. These prepara (BHT) tions were used in the study described in Example 1. Vitamin E 2.6 Stabilizer Polyethylene Compositions were prepared by injection molding. Two Glycol Succinate formulations were prepared: a medium load composition (TPGS) Shell (coating) 1OO 1OO 20 tested in three different tablet lengths; and a high load formu Ethylcellulose 87.O 87.0 Coat material lation tested in 9 mm length unit of half the volume. The Cetostearyl 12.O 12.0 Plasticizer medium load formulations were shown to release in dissolu alcohol tion test (USP2, pH 6.8, 50 RPM) with durations that were Titanium dioxide 1.O 1.0 Coloringstabiliser agent, UV proportional to the tablet length. The high load formulation 25 was adjusted by chemical formulation to a release time that was intermediate of the medium formulation release times. TABLE 16

Formulation A1-A3

Formulation Formulation Formulation A1 A2 A3 20 mg 20 mg 20 mg medium load medium load medium load 6.0 mm, length 7.5 mm, length 9 mm, length Quantity per Quantity per Quantity per unit unit unit

Component Function (mg) (% w/w) (mg) (% w/w) (mg) (% w/w)

Matrix

Hydrocodone Active 2O 13.6 2O 13.6 2O 13.6 bitartrate ingredient Polyethylene oxide Carrier 77.8 S2.9 77.8 S2.9 77.8 S2.9 200,000 Polyethylene oxide Carrier 14.7 1O.O 14.7 1O.O 14.7 1O.O 300,000 Poloxamer 188 Co-carrier, 23.5 16.O 23.5 16.O 23.5 16.0 Plasticizer Poloxamer 407 Co-carrier, 5.9 4.0 5.9 4.0 5.9 4.0 Plasticizer Butylhydroxytoluene Antioxidant, 0.7 O.S 0.7 O.S 0.7 O.S Stabilizer Mannitol Carrier, 4.4 3 4.4 3 4.4 3 Stabilizer

Total, matrix 147 1OO 147 1OO 147 100 Shell (coating)

Ethylcellulose Coat 80.9 87 95.7 87 145.3 87 Cetostearyl alcohol Plasticizer 11.2 12 13.2 12 2O.O 12 Titanium dioxide Colorant O.93 1 1.1 1 1.7 1 Total, shell (coating) 93 1OO 110 1OO 167 100

Total 240 2OO 257 2OO 314 2OO US 9,023,394 B2 71 72 TABLE 17 Day -1, when the first administration of co-medication nal trexone was given) and were discharged from the clinic on Formulation B1 Day 11, after the 36.0-hour post-dose blood draw. Subjects 20 mg high load came back for all subsequent blood draws on Days 12, 13, 14, (9.0 mm length) and 15. Naltrexone is an opioid receptor antagonist. Quantity per unit The number of subjects that enrolled, randomised and Component Function (mg) % Wiw completed the study was 18 (8 females and 10 males). Matrix TABLE 19 10 Hydrocodone bitartrate Active 2O.O 26.2 ingredient Treatment Polyethylene oxide 200,000 Carrier 40.7 53.3 Study Drug Co-medication Polyethylene oxide 300,000 Carrier 7.6 1O.O Poloxamer 188 Co-carrier, 7.6 1O.O Name Egalet (R) morphine Naltrexone hydrochloride Plasticizer 15 Formulation A (Revia (R) Butylhydroxytoluene Antioxidant, 0.4 O.S Unit dose 30 mg 50 mg Stabilizer Regimen single dose of 1 x 30 mg single dose of 1 x 50 mg film controlled release dosage coated tablet by oral administration Total, matrix 76.3 1OO.O unit by oral on the following days: Shell (coating) administration for 10 Day -1, 12 hours before the first consecutive days morphine administration; Days 1 Ethylcellulose Coat material 79.8 87.O (Days 1 to 10) through 10:1 hour before each Cetostearyl alcohol Plasticizer 11.0 12.O morphine administration; Day 11: Titanium dioxide Colorant O.9 1.O approximately 24 hours after the last morphine Total, shell (coating) 91.7 1OO administration (immediately prior to next dose) Total 168 2OO 25 The following pharmacokinetic parameters were calcu lated for morphine: AUCo., T. Steady state C, steady TABLE 18 state C. PTF, AUCota T2 ... and K. The pharmacoki Formulation 30 netic parameters listed above were also calculated for mor phine-3-glucuronide and morphine-6-glucuronide. Addi A1 A2 A3 B1 tional pharmacokinetic parameters were MRT, HVD and 6.0 mm 7.5 mm 9.0 mm 9.0 mm length length length length T-7s (for morphine only). Also the protraction index was Parameter O8-O188-113 O8-O189-113 O8-O190-113 O8-O191-113 calculated for each individual with regard to the morphine 35 concentration profile Release area 20.8 16.6 13.8 7 (mm) For purposes of evaluating safety, adverse events, vital Dimensions signs (including pulse oxymetry and ECG measurements), (mm) and standard laboratory evaluations were conducted for each individual. Length 6.O 7.5 9.0 9.0 40 Short 4.7 4.3 4.4 3.4 A single arm, non-comparative study, formal statistical diameter analyses were not performed for the PK endpoints. Endpoints Long 9.4 8.5 8.3 S.6 are Summarized and represented by N. arithmetic and geo diameter metric mean, median, standard deviation, minimum and maximum. FIG. 12 shows the release times for hydrocodone versus 45 The attainment of steady state was assessed based on log tablet length. transformed pre-dose plasma concentrations of morphine recorded on Days 4 to 10. In a repeated measures model with Example 4 Subject and day as factors, Day 10 concentration was com pared to Days 4 to 9, respectively. The first day with a non A Single-period, Multiple-dose, Single-centre, Phase I 50 significant difference to Day 10 is considered steady state. Mean and individual curves of untransformed pre-dose Trial Evaluating the Steady-state Pharmacokinetic Profile of plasma concentrations versus time (Days 4 to 11) were pro Egalet(R) Morphine 30 mg (Formulation A) Controlled duced. The steady state analysis was repeated, including time Extended Release Dosage Unit in Healthy Volunteers. Using since physical activity and time since last bowel movement as Naltrexone Blockade. 55 covariates in the model. The content of the Egalet(R) morphine 30 mg (Formulation Results A) controlled extended release dosage unit used in this study FIG. 13 shows the mean steady state morphine plasma is described in detail in Example 3 herein above in Table 14 concentration versus time curve (0-24 h). and was prepared according to the teachings of the present Steady state was obtained already after 4 days of adminis description. The shape was of the formulation used in this 60 tration of the Egalet(R) morphine 30 mg (Formulation A) study was a round, 9.0 mm long, with a volume of 150 mm extended release dosage unit. As four(4) days was the earliest and a cross section area of 8,335 mm. investigated time point, steady state may have been reached This study is also referred to as MP-EG-003 herein. even earlier. Both the mean and individual concentration vs. This was a single-centre, non-comparative, multiple-dose, time profiles indicate that the Egalet(R) morphine (Formula phase I trial, performed under fasting conditions. Subjects 65 tion A) dosage unit provided Sustained release of clinically were confined to the Clinical Research Facility from at least relevant amounts of morphine over a 24 hour period. The 14 hours before the first study drug administration (evening of results of this study also indicated that the Egalet(R) morphine US 9,023,394 B2 73 74 30 mg (Formulation A) extended release dosage unit was a Design candidate for providing either twice daily or once daily dos This was a single centre, open-label, single-dose, ran ing of morphine. In some Subjects, the morphine concentra domised, 5-way crossover, comparative bioavailability study, tion decreased to a relatively low level at the 24 h time point. performed under fasting conditions to evaluate dose-linearity The co-administration of naltrexone may have influenced the of the four strengths of Egalet(R) Morphine of Formulation B. PK-profiles and some of the PK endpoints. No severe, sig Treatments nificant, or serious adverse events were reported during the In each treatment period, Subjects were administered a study. single oral dose of either Egalet(R) Morphine of Formulation B (dosage unit of 30, 60, 100, or 200 mg) or Formulation A (two TABLE 20 10 tablets of 30 mg) controlled-release dosage units on Day 1, in accordance with the Subjects randomization sequence. The Pharmacokinetics - morphine content of the formulations are described in Table 14 herein Enrolled subjects 18 above. The geometry of the formulations are described in AUCo-2, (nmol *h,L) Table 15 herein above, 15 The treatment periods were separated by a washout of 7 Geom. mean 353 days. Min, Max 176-795 Treatment A: 1x30 mg Egalet(R) Morphine controlled-re TMa. (h) lease dosage unit of Formulation B (length 7.5 mm) Geom. mean 1.54 (08-0140-066). Min, Max OSO-S.O.S Treatment B: 1X60 mg Egalet(R) Morphine controlled-re C (SS) (nmol/L) lease dosage unit of Formulation B (length 7.5 mm) Geom. mean 31.6 (08-0138-066). Min, Max 141-593 Treatment C: 1x100 mg Egalet(R) Morphine controlled C (SS) (nmol/L) release dosage unit of Formulation B (length 7.5 mm) 25 Geom. mean 6.9 (08-0137-066). Min, Max 1.6-23.4 Treatment D: 1X200 mg Egalet(R) Morphine controlled C2 (SS) (nmol/L) release dosage unit of Formulation B (length 7.5 mm) (08-0139-066). Geom. mean 12.S2 Min, Max 2.19-27.3 Treatment E: 2x30 mg Egalet(R) Morphine controlled-re 30 lease dosage units of Formulation A (length 9 mm) (08 SS = steady state 014 1-066). To alleviate or avoid opioid side effects that are expected in Also, the Protraction index was determined, and the data opioid-naive subjects, naltrexone was administered as a 1x50 below in Table 21 are derived from the steady state profiles mg tablet with approximately 120 mL of water approximately obtained in the individuals, which participated in this study. 35 12 hours before morphine administration (Day -1), approxi mately 1 hour before morphine administration (Day 1), and TABLE 21 approximately 24 hours post-morphine administration (Day 2). Protraction index Methodology (AUCo-2,24 h), Cmax 40 A total of 39 healthy, adult non-smokers signed the study specific informed consent form and were confined for Period 1; of these subjects, 35 (18 males and 17 females) were enrolled and dosed in the study; 31 of these enrolled subjects completed the study. Prior to entering the trial. Subjects com 45 pleted all screening procedures. Upon arrival at the clinical facility for the confinement (Day -1) and once eligibility had been confirmed, Subjects were sequentially allocated a two digit Subject number that corresponded to the randomisation scheme. 50 All Subjects received standardised meals throughout dur ing their confinements, not less than 4 hours post-dose, approximately 9 hours post-dose, and an evening Snack approximately 13 hours post-dose. With the exception of the Volume administered at the time of the administration of Mean 55 morphine, fluids were not permitted from 1 hour before dos Min ing to 1 hours post-morphine dose, but water was permittedad Max libitum at all other times. Sample Collection Measurements of morphine plasma concentrations and Example 5 60 secondary analysis with morphine-3-glucuronide and mor phine-6-glucuronide plasma concentrations were performed A Single-Centre, Single-Dose, Randomised, Open-Label, at the following timepoints: pre-dose and 0.333, 0.667, 1.00, 5-Way Crossover, Dose-Linearity Study of Egalet(R) Mor 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 10.0, 12.0, 15.0, 18.0, phine 30, 60, 100 and 200 mg Controlled-Release Dosage 21.0, 24.0, 30.0, 36.0, and 48.0 hour post-dose. Units in Healthy Volunteers Using Naltrexone Blockade 65 Pharmacokinetic Parameters Under Fasting Conditions The following PK parameters were calculated and sum This study is also referred to as MP-EG-005 herein. marised by Standard non-compartmental methods for mor US 9,023,394 B2 75 76 phine plasma concentrations, morphine-3-glucuronide and where AUMC was the area under the first moment plasma concentrations, and morphine-6-glucuronide plasma curve from time 0 until the last valid measurement at the time concentrations. The morphine-3-glucuronide plasma concen pointt. C, was the last valid plasma concentration found at this trations and morphine-6-glucuronide plasma concentrations time point, t. were included for supportive information. % AUCo-1 1) AUCo. area under the concentration-time curve from time The proportion of AUC before T was found by 100 Zero to the last non-zero concentration (AUCo-z/AUCo.) 2) AUCo., area under the concentration-time curve from Pharmacokinetic Results time Zero to infinity (extrapolated) As displayed in FIG. 14, below, there was a clear increase 3) C. maximum observed concentration 10 in the concentration of morphine with the increase in dosage. The curves of 1 x60 mg Egalet RMorphine Formulation Band 4) Residual area: calculated as 100*(1-AUC/AUC). 2x30 mg Egalet(R) Morphine Formulation A were similar. 5) T. time of observed C. During the first 8 hours, the plasma concentration of 1 x60 mg 6) T2 ... elimination half-life Egalet(R) Morphine Formulation B was slightly higher than 7) K. elimination rate constant 15 that of the 2x30 mg Egalet(R) Morphine Formulation A. 8) MRT: mean residence time The metabolites morphine-3-glucuronide and morphine-6- 9) Proportion of AUC before T glucuronide concentrations were proportional between Pharmacokinetic Methods strengths. The PK endpoints were calculated individually for each Individual plasma concentration profiles for each subject Subject and dose based on the plasma concentrations obtained showed consistency across profiles for morphine, morphine on Days 1-3 (0-48 h) within each period. 3-glucuronide, and morphine-6-glucuronide concentrations AUCo within each subject. The area under the concentration-time-curve from time Oh For morphine, these relationships are also presented in until the last concentration sample at time 48 h, AUC were Table 22. The results for C displayed the same pattern as calculated by the linear trapezoidal method, using the actual 25 the results for AUCoas, and the results for AUCoas, and C. sampling time points. If the last blood sample was taken less confirmed the patterns displayed by FIG. 14. The relationship than 48 hours after drug administration, the 48 h values were between dosage and AUCo., was the same as for AUCoas. extrapolated using the terminal elimination rate constant, K, as described below. If the last sample was taken after 48 TABLE 22 hours, a 48 h value was estimated by interpolation. Interme 30 diate missing values remained missing (equivalent to inter Endpoints for Morphine polating between neighbouring points when calculating 30 mg 60 mg 100 mg 200 mg 2 x 30 mg AUC). Intermediate values below the limit of quantification Treatment Form B Form B Form B Form B Form A (LOQ) were assigned a value of LOO/2, while trailing values 35 at Co. 48 h (mol"h/L): below LOQ were assigned a value of Zero. Mean 300 681 1175 2437 618 AUCo-f Min-Max 110-535 364-1127 756-2189 1371-4176 203-1008 The area under the concentration-time-curve from time Oh C (nmol): until infinity was determined for profiles that did not return to Mean 19 43 73 168 35 Zero within 48 hours. AUCo. was calculated as the sum of 40 AUC and C/K, where Ct was the last sample above LOQ. Min-Max 8-40 23-69 38-138 71-277 16-72 T, and C Mean 381 823 1355 2702 728 T and C were derived from the samples 0-48 h after Min-Max 117-1668 414-2S82 784-2795. 1483-4528 209-1324 drug administration. Actual sampling time points were used Residual area (Pct.): for T. 45 Residual Area: Mean 13 13 11 9 13 Min-Max O-74 1-75 2-44 O-2O 1-43 Calculated as 100*(1-AUCAUCo.) Tmax (h): T1/2 ef The elimination half-life T was found by Ln(2)/K (for Mean 3 3 3 4 4 calculation of K, refer to the below) 50 Min-Max 1-6 1-5 1-10 1-10 0-24 Ke7: Elz) (h): The elimination rate constant, K, was the slope of the Mean 17 17 14 13 14 terminal part of the log-concentration-time-curve and was Min-Max 4-129 S-134 7-47 S-20 6-31 Elimination rate (1/h): found using log-linear regression. The final four plasma con 55 centrations above LOO were included in the calculation as a Mean O.O6 O.O6 O.O6 O.O6 O.O6 minimum. However, the log-linear plots of plasma concen Min-Max O.O1-0.17 O.O1-0.13 OO1-0.1O O.O3-0.14 O.O2-0.12 tration were inspected and a different selection of data points MRT (h): could have been chosen to ensure that the time period repre Mean 27 29 24 21 25 Min-Max 9-178 14-186 13-61 12-29 9-49 sented the terminal elimination phase. Actual time values 60 were used. Proportion AUCo. 1 MRT: (Pct.): The mean residence time was calculated as Mean 12 9 11 15 12 Min-Max 1-36 1-2O 1-28 2-33 1-54 MRTo-AUMCo., AUCo., where 65 For morphine-3-glucuronide and morphine-6-glucuronide plasma concentrations, the relationship between dosage and US 9,023,394 B2 77 78 AUCoas, C., and AUCo. was the same as for the mor TABLE 24 phine plasma concentrations. The pattern of the residual area and the elimination rate for morphine-3-glucuronide and Secondary Analysis of Morphine (Bioeciuivalence morphine-6-glucuronide concentrations was also similar as Means to that of morphine. For both morphine-3-glucuronide and morphine-6-glucuronide concentrations, the mean T was Form. B Form B. Form A 4 hours. (1 x 60 Form. A 90% Primary PKAnalysis (Dose-linearity) mg) (2 x 30 mg) Ratio CI p-value From the descriptive Summaries of AUCoas and C in 10 Full PK data Set: Table 23, it was clear that a dose response relationship was AUCo. 48) 642.3 583.0 10.2 (102.7, 118.2) 0.0235 present for AUCoas and C. (nmol * h L) AUCo. if 755.2 676.8 11.6 (100.9, 123.5) 0.0749 TABLE 23 (nmol * h L) C (nmol/L) 4.O.S 33.3 21.7 (113.0, 131.2) <.0001 15 Completers only: Primary Analysis of Morphine (Dose-Linearity) AUCo-Ash) 654.7 591.3 10.7 (103.0, 119.1) 0.0218 Coefficient 90% Confidence (nmol * h L) for log- Interval AUCo. if 772.2 693.6 11.3 (100.2, 123.7) 0.0945 (nmol * h L) dose Estimate Sto. Err. LOWe Upper C (nmol/L) 41.1 33.4 22.9 (113.8, 132.8) <.0001 PKSet-tail less 20%: Full PK Data Set: AUCo. if 714.4 624.9 14.3 (104.6, 125.0) 0.0141 (nmol * h L) AUCO Ash) B 1171 O.O2281 O792 1550 (nmol * h L) 25 AUCo i? B O806 O.O.3317 O225 1358 (nmol * h L) Endpoints are log-transformed before analysis, and results Cmax B 1365 O.O2297 O983 1747 are transformed back and presented as ratios. The model Completers Only: includes period and treatment as fixed effects and Subject as a random effect. 30 AUCO Ash) B 1185 O.O2310 O8O1 1569 Estimates and comparisons are based on the full model with (nmol * h L) all treatments included. AUCo i? B O826 O.O3376 O26S .1387 (nmol * h L) The mean is the geometric mean estimated from the model. C B 1349 O.O2310 O96S 1733 ex Secondary PK Analysis of 1x30 mg Formulation B Versus 35 1x30 mg Formulation A Table 23 presents the analysis of dose-linearity for mor A secondary analysis of PK parameters between the 1x30 phine concentration for AUCoas and C. mg Formulation B and a 1x30 mg Formulation A was com pleted, with the results of this analysis shown in Table 25. As The table showed that dose-linearity could be assumed, as 40 shown in Table 24, for all endpoints based on morphine the 90% confidence interval for B was fully contained within plasma concentrations, the 90% confidence for the estimated the interval 0.80-1.25 for AUCoas, AUCo., as well as for ratio of means lay within the boundaries of 0.80 to 1.25, and C, both for the full PKanalysis set and for completers only. none of the ratios were statistically significantly different The estimates of coefficient for the log-dose, B, for the three from 100. parameters ranged from 1.08 to 1.14. This indicated that the 45 bio-availability increased slightly more than proportionally TABLE 25 with dose. However, since the confidence intervals were within the regulatory acceptance limits, this slight deviation Secondary Analysis of Morphine PK Parameters - 1 x 30 mg was not considered clinically important. Formulation B versus 1 x 30 mg Formulation A The analysis of morphine-3-glucuronide and morphine-6- 50 Means glucuronide concentrations confirmed the results for the mor Form. B phine plasma concentration, as all 90% confidence intervals (1 x 30 Form. A Form B. Form A were contained within the interval 0.80-1.25 and all estimates mg) (1 x 30 mg) Ratio 90% CI p-value of B were slightly larger than 1. 55 The co-administration of naltrexone may have influenced Full PK data Set: the PK-profiles and some of the PK endpoints. AUCo. 48) 277.8 291.5 95.3 (88.9, 102.2) 0.2551 (nmol * h L) Secondary PK Analysis of 1 x60 mg Formulation B Versus AUCo. if 326.5 338.4 96.5 (87.3, 106.7) 0.5569 2x30 mg Formulation A (nmol * h L) 60 C (nmol/L) 18.0 16.6 108.2 (100.5, 116.6) 0.0811 A secondary analysis comparing PK parameters provided Completers only: by the 1x60 mg Formulation B and the 2x30 mg Formulation A was conducted. The results of the secondary analysis of AUCo-Ash) 2822 295.7 95.5 (88.8, 102.6) 0.2899 morphine are presented in Table 24, which shows that the (nmol * h L) AUCo. if 332.6 346.8 95.9 (86.3, 106.6) 0.5114 estimated ratios of means for AUCoast, and AUCo., were 65 (nmol * h L) 110.2 and 111.6, respectively, and the estimated ratio for C. C (nmol/L) 18.3 16.7 109.4 (101.3, 118.2) 0.0547 was 121.7. US 9,023,394 B2 79 80 TABLE 25-continued tapered, the length of the matrix is in the range of 8.0 to 15 mm, the matrix composition comprises (i) hydroc Secondary Analysis of Morphine PK Parameters - 1 x 30 mg odone and (ii) at least one polyglycol, and the matrix Formulation B versus 1 x 30 mg Formulation A composition exhibits a release rate of the hydrocodone Means from the matrix in ethanol that is equal to or lower than Form. B the release rate of the hydrocodone from the matrix in (1 x 30 Form. A Form BForm A water, and b) a coating Substantially surrounding the matrix compo mg) (1 x 30 mg) Ratio 90% CI p-value sition and having one or two openings exposing at least 10 PKSet-tail less 20%: one Surface of the matrix composition, the coating being Substantially impermeable to an aqueous medium, AUCo i? 296.8 312.4 95.0 (86.5, 104.2) 0.3604 wherein the tablet provides controlled release of the hydro (nmol * h L) codone over an interval of 24 hours, 15 wherein the tablet provides a C of hydrocodone reached Formulation A (130 mg) is derived by dividing AUC and no earlier than 18 hours after last administration, and C by 2—since two tablets were administered. wherein the tablet is resistant to isolation of the hydroc Endpoints are log-transformed before analysis, and results odone by any of crushing of the tablet, melting of the are transformed back and presented as ratios. The model tablet, and ethanol extraction. includes period and treatment as fixed effects and Subject as a random effect. 2. The tablet according to claim 1, wherein the matrix has Estimates and comparisons are based on the full model with a cross section with an area in the range of 1 to 75 mm. all treatments included. 3. The tablet according to claim 1, wherein the matrix has The mean is the geometric mean estimated from the model. a cross section with an area of at least 20 mm. Yet another explorative analysis was comparing the 24 4. The tablet according to claim 1, wherein the matrix has hour plasma concentrations of morphine from formulation B 25 a length of 8 to 10 mm. to formulation A. The ratio between 60 mg Egalet(R) Morphine 5. The tablet according to claim 1, wherein the matrix has Formulation Band 2x30 mg Egalet(R) Morphine Formulation a length of 8.5 to 9.5 mm. A at hour 24 was 116.0% (CI: 98.5%-136.7%), p=0.1351. 6. The tablet according to claim 1, wherein the coating Safety Results comprises two openings each exposing one end of the matrix. A total of 105 treatment emergent adverse experiences 30 7. The tablet according to claim 1, wherein a therapeuti (TEAEs) were reported by 17 of the 24 subjects who received cally effective response is achieved over the entire interval at least one dose of the study medication (safety population). between once daily administrations. No adverse events were severe, significant, or serious. 8. The tablet according to claim 1, wherein the tablet pro No safety issues were observed with respect to clinical vides a steady state trough of hydrocodone that is at least 20% laboratory results and vital signs results. 35 of steady state C. No relevant differences were observed among the treat 9. The tablet according to claim 1, wherein the tablet pro ment groups with respect to mean values and changes from vides a steady State trough of hydrocodone that is in a range of baseline for vital signs and clinical laboratory results. 30 to 80% of steady state C. As the 90% confidence intervals for the regression coeffi 10. The tablet according to claim 1, wherein a 1 point cient of the log-dose for AUCoast, and C were contained 40 where a plasma concentration of hydrocodone of 50% of within the interval 0.8-1.25 for morphine, dose-linearity was steady state C is reached occurs 0.5 to 2.5 hours after last demonstrated. Since the estimated coefficient of the log-dose administration. for AUCoast, as well as C, were larger than 1 and the lower 11. The tablet according to claim 10, wherein the tablet limit of the 90% confidence interval was larger than 1, there provides controlled release of hydrocodone such that a 2" was some statistical evidence of over-proportionality. Com 45 point where a plasma concentration of hydrocodone of 50% bining these two observations, some deviation from dose of steady state C is reached occurs no earlier than 12 hours proportionality was present, but in the light of the protocol after last administration. defined limits, this deviation was concluded not clinically 12. The tablet according to claim 1, wherein the tablet relevant. Evaluating the slight deviation from proportionality provides controlled release of hydrocodone in a manner that 50 results in a mean residence time (MRT) of at least 11 hours. between the dose levels, Table 26 gives the ratios between 13. The tablet according to claim 1, wherein the tablet geometric means after adjusting for dose. provides controlled release of hydrocodone in a manner that results in a T of 3 to 6 hours after last administration to a TABLE 26 steady state individual. Ratio of 55 14. The tablet according to claim 1, wherein the tablet Geometric provides a hydrocodone protraction index of at least 0.40. Means 60 mg 30 mg 100 mg/60 mg 200 mg/100 mg 15. The tablet according to claim 1, wherein the tablet AUCo-48 1.16 1.03 1.04 delivers sufficient hydrocodone in a controlled manner over a AUCo.; 1.15 1.00 1.01 24-hour period to achieve pain relief over a 24-hour period. C 1.14 1.01 1.16 ex 60 16. The tablet according to claim 1, containing a dosage of hydrocodone in the range of 10 to 500 mg. 17. The tablet according to claim 1, wherein the polyglycol The invention claimed is: is a water soluble crystalline or semi-crystalline polymer. 1. A tablet for oral delivery of hydrocodone, the tablet 18. The tablet according to claim 1, wherein the matrix comprising: 65 comprises at least one polyglycol that is a homopolymer. a) a matrix composition having a cylindrical shape with 19. The tablet according to claim 1, wherein the matrix two ends, wherein each of the two ends is optionally comprises at least one polyglycol that is a copolymer. US 9,023,394 B2 81 82 20. The tablet according to claim 1, wherein the total con 30. The tablet according to claim 1, wherein the coating is centration of the at least one polyglycol included in the matrix insoluble in an aqueous medium. composition is from 5 to 99% w/w. 31. The tablet according to claim 1, wherein the coating 21. The tablet according to claim 18, wherein the at least comprises one or more polymers selected from the group one polyglycol is a polyethylene glycol and/or a polyethylene consisting of Starch based polymers, cellulose based poly oxide. mers, synthetic polymers, and biodegradable polymers. 22. The tablet according to claim 21, wherein the polyeth ylene glycol and/or polyethylene oxide has a molecular 32. The tablet according to claim 1, wherein the coating weight from 20,000 to 700,000 daltons. comprises one or more polymers selected from the group 23. The tablet according to claim 1, wherein the matrix consisting of ethyl cellulose grade 20, ethyl cellulose grade comprises at least two different polyglycols, wherein the 10 100, polylactic acid (PLA), Cornpack 200, polycaprolactone, different polyglycols are selected from the group consisting PEO 7000000, and polyhydroxybuturate. of polyethylene oxides. 33. The tablet according to claim 1, wherein the coating 24. The tablet according to claim 23, wherein one polyeth comprises an ethyl cellulose selected from an ethyl cellulose ylene oxide has an average molecular weight in the range of of grade 20 and an ethyl cellulose of grade 100. 150,000 to 250,000 daltons and the other polyethylene oxide 15 has an average molecular weight in the range of 250,000 to 34. The tablet according to claim 1, wherein the coating 350,000 daltons. comprises one or more biodegradable polymers, selected 25. The tablet according to claim 18, wherein the concen from the group consisting of polylactic acid and polycapro tration of homopolymer in the matrix composition is from 5 to lactone. 90% W/w. 35. The tablet according to claim 1, wherein the coating 26. The tablet according to claim 19, wherein the copoly comprises at least 85% w/w polymers, wherein the polymers mer is a poloxamer that has an average molecular weight are selected from the group consisting of biodegradable poly selected from the group consisting of 2,000 to 30,000 daltons. mers and cellulose based polymers. 27. The tablet according to claim 19, wherein the matrix 36. The tablet according to claim 1, wherein the coating comprises one or more poloxamers. 25 comprises one or more plasticizers. 28. The tablet according to claim 27, wherein the matrix 37. The tablet according to claim 1, wherein the tablet is comprises only one poloxamer and has a length of 8.0 to 10 formed by injection molding. . 29. The tablet according to claim 19, wherein the concen 38. The tablet according to claim 1, wherein the tablet is tration of copolymer in the matrix composition is from 1 to formed by extrusion. 20% WFw.